Yeah, if you're just going to pick up one book, I've got to second (or third?) the Spell Compendium, Magic Item Compendium, or Unearthed Arcana. The first two are great, widely-applicable resources for both PCs and NPCs, while the last is an awesome toolboxe for customizing the most basic rules of your game (although, personally, I'd call it a starting point more than anything else).
But if you'd rather just throw a new and interesting subsystem into your game to give the players something cool to try out, or to give your campaign a unique feel, there are always the Expanded Psionics Handbook, Magic of Incarnum, Tome of Magic, and Tome of Battle. Each one of those books offers a few new base classes which use a totally new magic (or magic-like) system (or, in the case of ToM, three new magic systems), which could be really great if your players are tired of the usual elements of D&D, or if you want to introduce antagonists in your world with an exotic array of abilities.