It really depends on what you mean by "most popular", most watched, or most widely known, and are you talking currently, and do animes that haven't been here long (or at all) count?
Right now, I'd say the top 5 would be:
1. Inuyasha
2. Pokémon
3. Naruto
4. FMA
5. Zatch Bell
All-Time though:
1. DBZ
2. Pokémon
3. Inuyasha
4. Sailor Moon
5. Yu-Gi-Oh
It's hard to even compare Pokémon (and Yu-Gi-Oh even) to a lot of the other animes, since most animes that do well in the US are aimed at an at least slightly older audience.
Most of the (for example) Naruto auidience has known about Naruto for quite a while, and a big chunk of them have already downloaded, or otherwise seen episodes of the show, so you don't have as many Naruto fans waiting for Saturday to see an episode they probably saw last year. Whereas, probably around 95% the Pokémon audience, sees episodes for the first time every Saturday.
erm....you're all kidding me, right? Pokemon is not a popular anime. Nor is Yugioh. Want proof? Go to an anime convention, tell me how many people you see dressed up as a Pokemon character or a Yugioh character. Then tell me how many people you see dressed up as Naruto characters.
Once again, look at the fan-base. Pokémon could have 50 million fans, but if they're all between the ages of 8-11, you won't see them at an anime convention, Naruto could have a fraction of that, but if they're all 18 years old w/a job and money, you'll probably see a bunch at an anime convention.