'SNL' is back. And it could be its highest-stakes premiere yet.

Eighteen days after 9/11, New York City Mayor Rudy Giuliani took the stage at Studio 8H inside NBC's Rockefeller Center headquarters for the first episode of "Saturday Night Live" since the terrorist attacks.

It was a solemn cold open. The mayor, flanked by firefighters and police officers, implored viewers to carry on in the face of tragedy. Paul Simon, wearing an FDNY hat, performed a melancholic rendition of "The Boxer."

But the grave mood was leavened with humor, leading to one of the most memorable moments in the show's modern era. "SNL" chief Lorne Michaels joined the mayor on stage and asked him: "Can we be funny?"

Giuliani's deadpan reply: "Why start now?"

The premiere of the show's 46th season this weekend will take place against a similar backdrop of national mourning and crisis. More than 200,000 people across the country have lost their lives to Covid-19. Millions have been infected. The economy is devastated. President Donald Trump and first lady Melania Trump, meanwhile, have tested positive for the coronavirus, throwing the White House and the presidential campaign into turmoil.

The challenges for America's marquee sketch show are stark: How do you pull off 90 minutes of broad comedy and political satire in the middle of a pandemic and a public health emergency at the highest reaches of American government? Can you joke about the president when he is battling a deadly virus?

"The degree of difficulty just went up a hundredfold," said James Andrew Miller, co-author of "Live From New York," an oral history of "SNL."

Michaels, who has presided over "SNL" since the show debuted in 1975 (with the exception of a brief period in the 1980s), suggested in an interview with The New York Times last month that he feels a responsibility to provide "sanity" and "community" in times of national distress.

"We did a show with anthrax in the building. We did a show after 9/11," Michaels said. "That's what we've always done. To our audience, it's really important we show up."

But this year, even showing up — and in particular, returning to the high-stakes live format — is no simple matter. The coronavirus pandemic, which forced "SNL" to suspend live broadcasts in March and wrap its previous season with three remotely-produced episodes, has thrust the show into a tangle of unprecedented creative obstacles and logistical hurdles.

"There are numerous challenges that manifest themselves in everything: the construction of sets, makeup, wardrobe, the choreography that goes on backstage," Miller said.

"It's not simple, and it's going to require significant adjustments," Miller added.

The jarring new Covid-era reality for the late-night institution was plain to see in a pair of photos posted this week on the show's official Instagram account.

The first photo shows Chris Rock, the host of the season premiere, leafing through a script while wearing a white mask. The second photo provides a zoomed-out view: cast and crew members individually seated at folding tables spaced 6 feet apart.

In a recent interview with New York magazine, Michaels said he had been immersed in meetings focused on "the sheer physical challenge of what we can do within protocols."

"The physical problems of doing it — number of people who can be in the studio, number of people who can be in the control room, how you separate the band so that they're not in any jeopardy — all of those are part of the meetings," Michaels said.

In the Covid era, producers of late-night comedy shows and daytime talk shows have come up with various ways to create a sense of normalcy. "The Tonight Show" returned to 30 Rock without a studio audience. Stephen Colbert and Trevor Noah host their shows from their homes. "The Kelly Clarkson Show" features a virtual audience.

For their part, the producers of "SNL" are moving forward with plans for a "limited in-studio audience," according to a statement from NBC's entertainment unit. The show was working closely with New York Gov. Andrew Cuomo's office on the details, the statement said.

Cuomo's office, along with the New York Health Department, provided "SNL" with criteria it would need to meet in order to invite an audience back into Studio 8H, a state official told NBC News. The criteria, outlined on a state website, mandates that indoor production facilities should not exceed 50 percent occupancy, among other rules.

The ticketing website 1iota recently allowed prospective audience members to register for a "pre-screening process" to "determine eligibility to participate" in the show's audience. The listing said anyone selected would need to take a mandatory Covid-19 test, submit to a temperature check and wear a face covering, in addition to other guidelines.

Miller stressed that an in-studio audience is integral to the format and formula of "SNL," describing it as the "oxygen and lifeblood" of the show.

"I can't tell you how many cast members I've spoken with over the years who have talked about the impact of the audience: how it shapes their performance and gears them up," said Miller, who alongside TV critic Tom Shales spoke to dozens of "SNL" players for the oral history book.

But will cast members be required to wear masks during sketches and other on-air bits? Michaels provided some clarity to the Times, explaining that performers "will wear masks until the moment the red light goes on, at which point the Velcro back will be taken off."

If the first stretch of the new season — "SNL" begins with five consecutive episodes Oct. 3, 10, 17, 24, 31 — comes off with few technical glitches or obvious hiccups, the show might provide a model for concerts, Broadway shows and other forms of live entertainment that have been brought to a standstill by shutdowns related to Covid-19.

"I think people in the television industry will … come away with a better understanding of what they can do and what they can't" during the Covid-19 crisis, Miller said. "I think a lot of people will be watching for that."

But as with any season of a show widely known for its political satire and ripped-from-the-headlines riffs, "SNL" is expected to grapple with more than Covid-era restrictions when the clock strikes 11:30 p.m. Saturday.

The show is slated to hit the airwaves in the final stretch of a fierce presidential campaign unlike any other, a race that supplies an inordinate number of comedic possibilities.

The first presidential debate, a chaotic melee during which Trump repeatedly interrupted and shouted over former Vice President Joe Biden, likely provided the show's writing team with particularly fertile ground for parody. But the president's coronavirus diagnosis, announced early Friday, might have moved the show's writers — and regular Trump impersonator Alec Baldwin — to potentially soften their edges when it comes to mocking the president.

Nick de Semlyen, author of the book "Wild and Crazy Guys: How the Comedy Mavericks of the '80s Changed Hollywood Forever," speculated on Twitter that the show might need to cut much of its Trump-centric material given his diagnosis.

"Presumably they’re going to have to scrap a lot of it," De Semlyen wrote.

Jim Carrey has been tapped to play the Democratic nominee — filling the shoes of Woody Harrelson, who played Biden a few times during the primary campaign, and former cast member Jason Sudeikis, who portrayed him during President Barack Obama's administration.

"With this election, it's not an original thought or statement to say that there's a lot at stake," Michaels told New York magazine. "Going back to Ford/Carter, we've had a voice, and we will try as hard as possible to maintain that voice."