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WEIRD SCIENCE Depp has made a career of playing oddballs like Ed Wood and Hunter S. Thompson

In ''Once Upon a Time in Mexico'' (Sept. 12), a sequel of sorts to 1995's ''Desperado,'' Johnny Depp plays a sociopathic CIA agent who hires Antonio Banderas' El Mariachi to sabotage a political assassination on the Day of the Dead. Not surprisingly, Depp -- known for the quirky qualities he's brought to such films as ''Edward Scissorhands,'' ''Ed Wood,'' and ''Fear and Loathing in Las Vegas'' -- had certain ideas about his ''Mexico'' character. ''Before he even got there he called and said, 'I imagine this guy wears these really cheesy tourist shirts,''' recalls director Robert Rodriguez, who admits that he still had no idea what he would be in for.

Before showing up on the set in San Miguel de Allende, Mexico, Depp called his sister in Florida and had her scour the area for T-shirts with silly slogans like ''CIA: Cleavage Inspection Agency'' and ''I'm With Stupid,'' featuring an arrow pointing below the belt. ''Florida has no shortage of idiotic T-shirts,'' says Depp. ''I was also desperately looking for one of those baseball caps that say ''S---head'' and has a picture of a coil of dookie on the bill.'' Some of Depp's other flourishes for his character included carrying around a Judy Garland biography (''I just kind of figured that this guy might have a sideline obsession with Broadway'') and wearing an assortment of obvious disguises (''That's why I brought along all my wigs and fake mustaches'').

Depp has been an idiosyncratic presence since his career started in the late '80s, when he pulled stunts on the ''21 Jump Street'' set (wearing a George Washington powdered wig, wrapping rubber bands around his tongue) in an attempt to get out of his contract and the teen idol reputation he was eager to shed. And even now, at 40, Depp still carries the same merry prankster attitude of a young punk. His jeans are ripped at the knee, his boots so scuffed it's hard to discern what color they might have once been, and he's covered in silver rings, charm necklaces, and conversation-piece tattoos. He has a dozen of them. He got the first at 17 (an Indian chief on his right bicep) and the 12th just recently (his son's name, Jack, on his right forearm). When he laughs, which is often, you can still make out the pair of shiny gold-capped teeth he flashed in ''Pirates of the Caribbean'' -- the biggest hit of his odd 20-year career.

Depp still seems a bit dazed by ''Pirates''' success and all the attention he's gotten for his swishing, sozzled performance. So it's strange to hear him explain how his mascara-clad riff on Keith Richards almost got him fired. ''There were a couple of high-end Disney executives who were fine with what I was doing,'' he says. ''But there were a couple who were very worried.... You know, like, 'He's ruining the movie! Why is he acting like that? What's he doing with his hand? Is the character a complete homosexual?' There was a lot of that going on for a solid month and a half. And I understood their worries, but I felt so in tune with this character and so confident that what I was doing was right that I had to say, 'Look, I understand your fear. But you've hired me to do a job. You know what I've done before, so you know it's going to be something along these lines. So please trust me. And if you can't trust me then you probably should replace me.'''

When ''Pirates'' surpassed $100 million at the box office, then $200 million, then $250 million, Depp says he would get congratulatory phone calls from the same folks who had initially questioned his performance. He says those calls were ''deeply satisfying.'' Now all is forgiven and he even hopes to do a sequel. It would be his first. After all, Depp's never been in a movie that's done well enough to warrant a sequel. Not that his fans mind. In Depp, they've seen an artistic martyr -- Hollywood's very own Saint Jude, patron saint of cinematic lost causes. Until now, though, studio heads have had a less charitable label for it: box office poison.

''I think he's probably the premier actor of his day,'' says Miramax head Harvey Weinstein, whose Dimension Films division co-financed ''Mexico'' with Columbia Pictures. But, he adds, ''I think he's been frozen out for years. I think he was looked at as too risky for a lot of the top stuff. A lot of people are going to be kissing his butt now. But what they don't understand about Johnny is that he can smell BS 10 miles away. The same guys who a year ago were saying 'Him? Are you kidding? He's box office poison' now [think] he's the hottest thing in the universe.''

The actor himself swats away these kinds of observations about opening weekends and tracking numbers. ''It's really none of my business,'' says Depp, who enjoys a life far from Hollywood with his girlfriend, 30-year-old actress-singer Vanessa Paradis, and their two children Lily-Rose, 4, and Jack, 1, in the south of France. When pressed why movie studios keep hiring him since his films tend to be commercial disappointments, he shrugs, ''I don't know. Because they're mad. They're insane. All I can say is for a guy like me, who's been dangling in this business for the last 20 years, to finally have something hit, it's unexpected and very touching.''

After the success of ''Pirates of the Caribbean,'' Depp can probably channel anyone he wants in any movie he pleases. Comic-book heroes, franchise no-brainers -- easy paydays for easy performances. Instead, he seems hell-bent on continuing to heed the call of Saint Jude. Already in the can is ''J.M. Barrie's Neverland,'' a drama in which he plays J.M. Barrie, the author of ''Peter Pan.'' And right now he's working on ''Secret Window,'' an adaptation of a Stephen King novella, where he plays a writer being stalked by a deranged hack accusing him of stealing his ideas.

After that, there are a couple of possibilities. One is picking up where he left off on Terry Gilliam's ''The Man Who Killed Don Quixote'' -- the movie whose disastrous unraveling was documented earlier this year in ''Lost in La Mancha.'' Another possibility is reuniting with frequent collaborator Tim Burton to remake ''Willy Wonka & the Chocolate Factory.'' While it's not a done deal, Depp sees ''Wonka'' as the ultimate without-a-net challenge. ''You'll never escape that memory that's seared into your consciousness of Gene Wilder as Willy Wonka,'' he admits. ''It was really amazing to watch as a kid growing up, and I've watched it with my kids. So it's just, Okay, where do I go from there? Gene Wilder did something very beautiful and it's time to take it somewhere else.''

Depp doubts that Burton will make him belt out musical numbers like Wilder did in the original, but he's not exactly opposed to the idea, either.

''Sure, why not?''

Because you've never sung before...

''That's all right.''

Aren't you scared of anything?

Pause...

''Clowns.''