Basic schoolboy electronics notes things are built from fundamental components (might want to add memristors and inductors onto that, though practical memristors are a bit thin on the ground).
My main concern, and it could well be a fatal one (as it is many times analogue electronics pokes into the digital world) would be timings issues and interference. Basic physics notes that longer distances come with delays, possibility for more interference (those nice long wires/traces going all over the shop are basically a recipe for cross talk and are antennas all by themselves), resistance drops needing corrections there (which also tend to come with timing/circuit hazard problems) and all that might flow from that. Some of this would necessarily involve more components to correct for it, though I don't know when that might achieve some kind of runaway issue you can't tame (or take a lesser emulation/simulation for -- cycle accurate and bug for bug is nice but not exactly necessary in all things) a la Amdahl's law for CPU cores.
This would get worse as transistor count increases -- 5000 transistors (high for 6502 aka NES, low for a Z80 aka master system and debatably gameboy) for even surface mount packed side to side is going to be quite large, never mind with connections. More transistors, which also usually comes with a higher clock speed (I assume we are going for real time and not basic output simulation/emulation) and thus shorter windows for error correction.