All standard layouts are crap to varying degrees (underused thumbs, overloaded pinkies, asymmetry of distances, etc), but we're used to them, so we use them.
I prefer that ANSI Enter is closer to my fingers than ISO, I prefer the more symmetric layout and the universal keycap set support. The last point alone is worth switching to ANSI.
ISO layouts have crap placement of important characters for coding, like (,),-,_,=,+,[,],{,},;,\, etc... they're all nicely accessible in ANSI without having to resort to weird AltGr combinations. I hate using Alt/AltGr for anything as it's positioned too far from both the thumbs and the pinkies to be used comfortably for any combinations. Short left Shift is stupid (have to stretch for all capitals and number key symbols can be a pain). It's because of this that I only use the right Shift.
Best layout = custom layout, but ANSI is definitely better than ISO in everything except number of keys.