Flask's import time side-effects and has global objects everywhere. It's great for a quick hackathon and a great eco-system, though arguably you can just use Pyramid for that.

In my experience, growing bigger with Pyramid has been much easier than it has been w/ Flask. We found ourselves writing most of Pyramid using Werkzeug when it would've made sense to start off with Pyramid in the first place.

Pyramid's design for extensibility and design decisions are solid and really make a difference if you're building a real app vs a toy app.