True. The code generated by https://cc65.github.io/ is pretty decent but there are a few places where hand-rolled assembler will perform much better when you need it. Although I've made things for 6502-based systems in C with this handy compiler (thanks cc65 contributors!).

Is there something intrinsic to how C handles addressing that makes segmented architectures more painful than they ought to be? Or maybe is there a language where segmented addressing is easier?

I hadn't really thought about it in a while. :)

Lisp is fine on 6502 though :-)