Depends what you want from reading him.... I would generally recommend starting with Small Gods to get a handle of how Pratchett writes. Skip some of the earliest books because he's still practicing how to get the world right and his voice isn't clear yet - you can go back and read them later. I'd start with Wyrd Sisters if you want to read the witches. Start with Mort if you want to find out about Death, and start with Guards Guards if you want to get a handle on The Watch.

If you don't mind YA and kids books, you can always read The Wee Free Men and go down the Tiffany Aching storyline, they're from 2003 onwards and well into Pratchett's awesome phase. They feature Granny Weatherwax, one of the best characters, and the Nac Mac Feegle (who first appear in Carpe Jugulum) but you'll pick up who they are as each Discworld novel is a standalone (sort of).

If you want to come into a more developed Discworld you could start with Going Postal and read the Moist Von Lipwig books, then go back through the cannon and see how the Discworld develops. Wherever you choose to start, give Pratchett a few books grace and enjoy his fondness for footnotes. :o)