I build my cities similar to Mark. I setup districts, or smaller towns spread around the map rather than jamming everything into one spot. This helps keep the load down it seems as each town has its own share of industry of some sort, commercial areas, and residential areas. The residents do travel between the different areas though as I found when I've followed CIMs around using the first person camera.
On my system, I see very little CPU usage and a bit of graphics usage which will increase and decrease depending upon where I am in my cities, as this most likely depends upon the quality of the assets - meaning overly built high-poly assets increase the graphics and CPU load more and increase the graphics usage as well. Graphics usage will of course increase if I pan around the camera since the assets need to load but then settle down to it's normal levels.
Curiously absent is a lot of disk access, however, RAM can get really, really peaked out at 30% which brings my total RAM usage up to around 85% for my system. I know I need more RAM which will help, but my budget is tight so the 32GB I have right now is all the system is going to get.