After the Montreal disaster, Handler spent the rest of her twenties working at small acting jobs between large doses of waitressing. But she did appear regularly on the Candid Camera–inspired Girls Behaving Badly, and her standout performance finally landed her a big TV gig—hosting On the Lot, a reality show in which aspiring filmmakers compete for a deal. But Handler soon quit. “It was a debacle,” she says. “As soon as I got on the set, I found myself thinking, What am I doing? This is so not who I am!”

By that time, Chelsea Lately was already in the works, and it launched the same year. The rest is herstory—except for continuing gibes from critics and rival performers that she landed the talk show because she was dating then–Comcast executive Ted Harbert, who supervised the E! network.

When asked about those accusations, Handler responds, “Ted Harbert is not responsible for me selling four books on the New York Times list. He’s not responsible for me selling out arenas. All he did was recognize talent. He put Roseanne Barr on the air. He put Brett Butler on the air. This is a guy who notices female comedians, and he noticed me. You don’t get a TV show because you’re sleeping with someone. That’s when you get a walk-on role as, like, a female police officer.”

No walk-on cop, Handler soon propelled herself into the comic stratosphere with such mordantly witty bits as one in which she reports on a Paris Hilton tweet: “Sad to leave [Brazil], but ready to go home and get back to work.” Handler waits a beat. “Work then responded on its Twitter: ‘I’ve never heard of Paris Hilton.’ ” But the comedian is also a person who craves serious conversation. She describes her appearance on Rosie O’Donnell’s short-lived talk show on OWN, during which she somberly discussed her abortion at age 16 as well as her brother’s death, as “my favorite interview ever.” What she likes, she says, is a format that gives you “a long time to talk and be real without necessarily being funny. I ran into Ellen DeGeneres, and she said, ‘Oh my God, I sent you a note about your interview with Rosie. It was just so amazing to see you like that. I wish I could do interviews like that.’ ”

Handler deeply admires other comedians who have the ability to be serious. “Will Ferrell is a perfect example of someone who isn’t ‘on’ all the time. Bill Maher has that ability also. It’s not like Robin Williams”—who notoriously can’t refrain from putting on a show in any setting—“who I would presume has major, major depression issues. I don’t know him personally, but that would be my guess.”

Is that guess based on her personal experience? “Oh no!” she insists. “I’m not a depressed person. I’m pretty even. I have my moments, and I can get very passionate about things. But I’m generally very happy. I mean, why wouldn’t I be, considering?” When I offer the Hollywood cliché that success doesn’t always bring happiness—exhibit A: Whitney Houston—Handler parries, “Well, that’s an issue about years and years of abuse. I don’t ever want to abuse something so much that I’m forced to give it up.” She pauses, then deadpans, with Catskills timing, “And that’s why I’m only going to have seven margaritas during this interview.”

But here’s the thing: Ever on a schedule (“I have a long day—I have to work out later and then go to a Grammy party”), Handler doesn’t have seven; she stops at one. Is this, then, another of her dirty secrets? Admits the most famous consumer of vodka since Agent 007: “I don’t drink as much as I should—or as much as people think I do. Mondays through Wednesdays I try to take it easy, and then on the weekends I do whatever I want. It’s more for diet than the actual drinking thing. You can’t drink like that and expect to be in at least somewhat decent shape. I mean, I love to go out and drink and have fun with my friends. But I’m not a mess.”