Question: I have some large resources that I only need for my simulator runs—I'd like to have them automatically excluded from all device builds. Is there any way to do this with Xcode 4 short of custom build scripts that copy the resources?

Answer: 
Targets dictate what's included in a product. Duplicate your target and create a scheme for it. Modify that target's membership.
Custom build scripts is your best friend in Xcode. Have the script delete the resource after the build and before the code sign.