ShedSkin is great if you don't want Python interoperability. Remember the excitement when they announced that Jython now runs Django? Cython allows you to run Django plus some optimized code, whereas there's currently no convenient way to make ShedSkin and CPython talk to each other. (And it's also the reason why hopes on PyPy are so high: A specializing JIT would allow you to combine all the flexibility and monkeypatching from CPython with the speed you normally only get from a compiler).