Jack Black, Jennifer Aniston, Halle Berry and Keanu Reeves - along with presidential nominees John McCain and Barack Obama - were among the stars participating in "Stand Up to Cancer," an hour-long, commercial-free fundraising show spearheaded by entertainment industry heavyweights whose lives have been touched by the disease.
"This is where the end of cancer begins," Anniston remarked to the crowd.
"This is an absolutely historic night, thanks to the unbelievable generosity of the three networks," producer and cancer survivor Laura Ziskin told the audience at the Kodak Theatre before the show began.
"We hope we're going to make you laugh, and I know we're going to make you cry, so I have some party favors," she said as she tossed packets of Kleenex into the crowd.
Cancer survivors Lance Armstrong and Elizabeth Edwards kicked off the program with statistics: Cancer kills 550,000 Americans and six million people worldwide each year.
"That's the equivalent of 9/11 every two days," Armstrong said.
Patrick Swayze, Billy Crystal, Salma Hayek and Christina Applegate urged viewers to call in and donate, while Neil Patrick Harris, America Ferrera, Christina Ricci and Kirsten Dunst answered phones. A visibly pregnant Jennifer Garner, along with Berry, Forest Whitaker and Casey Affleck, read personal accounts from those battling cancer.
Swayze suffers from pancreatic cancer.
He got a standing ovation as he said, "I stand here another individual living with cancer and I ask that we not wait any longer. And I ask only one thing of you, will you stand up with me? Will you stand up to cancer?"
Network news anchors Katie Couric, Charles Gibson and Brian Williams emceed the program, discussing advances in research and telling heart-wrenching tales of those struggling with the disease.
Couric lost her husband to colon cancer. "I just think it's so wonderful to see so many people get together and say, 'We're mad as hell and we're not going to take it anymore,' " she said.
Black provided a dose of comic relief: "I usually watch these things at home in my underwear," he said, adding that the celebrities answering phones may have some of the fattest pockets around.
"I'm going to make these gravy-trainers pony up," he said. "Who's got Spielberg's number? He's got a lot of dough."
Brad Garrett, who underwent a prostate exam on the show, said, "I can't believe that Fox is counter-programming against this!"
Charles Barkley shared his colonoscopy with viewers. The worst part of the experience? Fasting.
"I'm a fat guy. I don't like to go the whole day without eating," the basketball star said.
Many of the stars wore t-shirts in memory of loved ones lost to the disease, noted Early Show national correspondent Hattie Kauffman.
She added that survivors had shirts of their own, and a fighting spirit.
"Cancer is not the boss of me," Fran Drescher said. "You know what? You get it, you work on it, and you get it gone," Sharon Osbourne added.
The show featured musical performances by James Taylor and Sheryl Crow, Josh Groban and Monica Mancini, Melissa Etheridge with Sugarland, BeBe Winans and Jason Mraz. It also featured a performance by more than a dozen divas - including Beyonce, Mariah Carey, Mary J. Blige and Rihanna - who sang their new charity song, "Just Stand Up," via video from the Fashion Rocks show in New York.
Aniston helped close the program with a nod to Hollywood.
"In our world, the boy gets the girl, the hero defeats the villain, and cancer is no more," she said.
Skateboarder Tony Hawk, who lost his father to lung cancer 15 years ago and a close friend to a brain tumor last month, said he was just happy to participate.
"I'm here doing whatever they ask of me," he told reporters before the telethon began. "As long as I don't have to sing or dance, it's all good."
Ziskin, one of the event's organizers, has fought cancer since 2004. After seeing what "An Inconvenient Truth" did for environmental awareness, she wanted to make a documentary about cancer. But instead she teamed up with Couric, Sherry Lansing and other cancer community activists to put on the live telethon.
"Cancer is not in the closet anymore, and now that it's out of the closet we have to motivate the public to demand that as a country we do better," she said. "And if the country won't do it, we'll do it. We'll raise money ourselves and try to spend that money in a way that will lead to better, less toxic treatments that we can get to patients more quickly."
The aim of Stand Up to Cancer is to raise funds for "translational research," Ziskin said, which encourages scientists to collaborate rather than compete, translating basic science into applicable therapies for patients. She compared the approach to the Manhattan project.
"We took the best and brightest and locked them up in Los Alamos and said you can't leave until you split the atom and create, unfortunately, a bomb," Ziskin said. "This is no less a problem, with half a million Americans a year dying from this disease. If we take best and brightest, encourage them and reward them for working together, the answers will come much more quickly."