As you've no doubt already guessed, this is not an easy question. Everyone has their own favorites. I love anything to do with Sam Vimes, personally, so for my taste I'd say start with Guards! Guards! It's quite a good book in its own right, and the various guardsmen (and women, and dwarves, and trolls, and gnomes, and golems, and...) show up as background or minor characters in pretty much any of the books set in Ankh-Morpork so it's not a bad idea to know who they are.
I've never been as fond of the Witches sub-series, though I do enjoy those books quite a bit. I also agree that the Tiffany Aching books might make for a nice introduction. They're aimed at kids, sure, but the series matures with the character and the Nac Mac Feegle are as funny as anything Pratchett has ever devised. I'd put the series up against pretty much any so-called "adult" book I can think of, at least in the same weight class. They make for a very good example of the kind of mythic grandeur Pratchett is so good at blending with humor and realism, too.
For the more-or-less standalones, I can't fault those who suggest Going Postal. I just finished re-reading its sequel, Making Money. They're both great, and Going Postal especially is an excellent example of another of Pratchett's specialties, finding the nobility in everyday things. Another very popular standalone is Small Gods, which I think was excellent but have never personally wanted to re-read. It's many people's favorite of the entire series, though, and a pretty good introduction to the Discworld concept of religion.
The Death books are great, though I'm not much of a fan of Susan, which is annoying since she gets to be a bigger and bigger character as time goes on. Death himself is a truly amazing character, and he's got a great character arc over the course of his sub-series.
The Rincewind books start out maybe the weakest of all, but they surely do end strong. Interesting Times and especially The Last Hero are just great reads, and the latter might be my favorite Discworld book of all. You can't really appreciate it if you haven't read at least Interesting Times, though. Cohen The Barbarian is just an amazing character, and his ending was truly worthy of an epic song.
Hell, all the series are good. Pick one and dig in.