Variable-length instructions make life difficult for modern superscalar x86 processors. They must split the bytestream into instructions in advance to run instructions in parallel. This takes a lot of logic to analyze the instructions and find the length.
But it could be worse. The Intel iAPX 432 (1981) was supposed to be Intel's main processor. It had instructions from 6 to 321 *bits* in length so instructions weren't even byte aligned. The iAPX 432 was too complicated, went way over schedule, and was a commercial failure.