First of all, in what language are you writing this?
It's true that a crack-proof program is impossible to achieve, but you can always make it harder. A naive approach to application security means that a program can be cracked in minutes. Some tips:
If you're deploying to a virtual machine, that's too bad. There aren't many alternatives there. All popular vms (java, clr, etc.) are very simple to decompile, and no obfuscator nor signature is enough.
Try to decouple as much as possible the UI programming with the underlying program. This is also a great design principle, and will make the cracker's job harder from the GUI (e.g. enter your serial window) to track the code where you actually perform the check
If you're compiling to actual native machine code, you can always set the build as a release (not to include any debug information is crucial), with optimization as high as possible. Also in the critical parts of your application (e.g. when you validate the software), be sure to make it an inline function call, so you don't end up with a single point of failure. And call this function from many different places in your app.
As it was said before, packers always add up another layer of protection. And while there are many reliable choices now, you can end up being identified as a false positive virus by some anti-virus programs, and all the famous choices (e.g. UPX) have already pretty straight-forward unpackers.
there are some anti-debugging tricks you can also look for. But this is a hassle for you, because at some time you might also need to debug the release application!
Keep in mind that your priority is to make the critical part of your code as untraceable as possible. Clear-text strings, library calls, gui elements, etc... They are all points where an attacker may use to trace the critical parts of your code.