One technique I remember being used in DOS apps from many years ago was that the code would be encrypted in such a way that the next instruction to be executed would only be decrypted immediately before it was run. This was achieved by setting up the single step interrupt as the decrypter, and running the code in single step mode.

The fact that the code was encrypted meant the debugger couldn't disassemble it in any meaningful way, and also made it impossible to set a breakpoint (since the breakpoint would just end up being "decrypted" into some other opcode that would inevitably crash). The debugger also couldn't step through the code, because taking over the single step interrupt would prevent the decrypter from running, so you'd just be stepping through garbage.

The way I worked around this was by writing a debugger that could hook the single step interrupt in such a way that it still forwarded the interrupt onto the previous hook. I still couldn't set breakpoints, but I could step through the code, watching it decode itself as it proceeded.