I recently read Middlesex by Jeffrey Eugenides. Very American, and quite extraordinary -- not sure if it's a best, but it's very good.

I second All the King's Men (incredible portrait of ambition and corruption); Huckleberry Finn; Grapes of Wrath; Narrative of the life of Frederick Douglass (just finished it recently, amazing book!). I agree that Ayn Rand didn't write good novels, she wrote propaganda wrapped in a plot. I also agree that Moby Dick is too hard to read to be truly great; simplicity is underrated.

Poetry has to include Emily Dickinson, in addition to ee cummings -- I think between the two of them they transformed poetry forever.