TCG is not that great, so I hear--might not make the best starting point. But VMs do seem like a promising avenue. One obvious problem is register allocation:

TCG is not that great, so I hear--might not make the best starting point. But VMs do seem like a promising avenue. One obvious problem is register allocation: if guest has more registers than host, and you can predict branch X is hotter than branch Y, then spill Y's registers to keep X's in (host) registers.