I'm partial to the ATSF, (also BNSF), UP, WP, and SP in the deserts of the southwestern US. I like the BN/GN/NP/BNSF in the Pacific Northwest, too.
Most of the well-known locomotives on US RRs have been made, so finding models of your chosen RR should be pretty easy.
What era are you thinking about modeling? Also, think about what location(s) you would like to model.
Western US scenery is mostly mountains and deserts. The midwest is mostly flat praries with a few hills and sparce vegetation. Trees get very expensive, so you might want to go with the southwest or midwest, rather than the northeast or northwest, or southeast. An urban layout with tall buildings would be a lot of work, but I've seen some really detailed big cities on layouts.
You could also customize your own locomotives and rolling stock and do a fictional railroad. For example, there's a guy on Youtube, Tim, who is a real-life locomotive engineer for Norfolk Southern. He is working on his fictional Seaboard Central RR HO-Scale layout. He has a lot of locomotives that he has had repainted into SCRR liveries. Check out Tim's layout (Seaboard Central on Youtube). It's pretty awesome, and he goes into how he operates his layout just like a real railroad.