In my experience, as someone who runs a fairly hefty Python application, the biggest source of incompatibility is the C extensions. One that's a thorn in my sid

In my experience, as someone who runs a fairly hefty Python application, the biggest source of incompatibility is the C extensions. One that's a thorn in my side is psycopg2. There's a version that works with cffi, but then you're crossing your fingers hoping that it matches the main psycopg2 package in terms of functionality and security updates. I would gladly throw money at someone to figure out how to take the juicy compat bits from Pyston and bring them into Pypy.