1. Watch episodes 1-45 just to see how the core crew comes together.
2. Skip 46-47.
3. Watch 48-53. Loguetown. This is where it starts to get good.
4. Skip 54-61.
5. Watch 62-67. Laboon and Whiskey Peak. Good, good.
6. Skip 68-69.
7. Watch 70-135. Little Garden, Drum and Arabasta. This is where it gets truly excellent.
8. Skip 136-143.
9. Watch 144-206. Jaya and Skypiea. The only good filler (G-8) is included here.
10. Skip 207-226.
11. Watch 227-325. Water 7 and Enies Lobby. And it's still getting better!
12. Skip 326-336.
13. Watch 337-381. Thriller Bark. Some of the funniest parts.
14. Skip 382-384.
15. Watch 385--> onward and keep watching!
EDIT: Skip also 426-429; these are special episodes linked to movie 10. There's also some alternate universe episodes and recaps here and there, but you'll probably notice them immediately and skip anyway. Some fillers try to flow smoothly into actual story arcs, so you might need to watch the end of the previous filler episode to see the transition (226 to 227, for example).
Bonus tip: Use fast-forward button creatively during long fights.
Bonus tip #2: Don't watch the movies. Or if you must, watch only movie 10 after Thriller Bark.