I wasn't aware ZRS is now free/open source. I would need to look at what that brings to the table but it's unlikely to change my views. I'll check it out though and thanks for the heads up!

Ignoring ZRS- As your number of clients and transactions go up you're still bottlenecked in a single server. That's what I mean by doesn't scale. For various reasons (e.g. objects can refer to each other) you're basically stuck. A scalable database provide various means of growing as your load grows and ZODB does not.

There are a few problems with pickling. First of all it is slow. Under some assumptions there are faster ways of marshalling in Python. Secondly your granularity of access is the entire object. You can't just get a certain field out of a large object. Thirdly because objects in the client cache are pickled you are spending a whole lot of time serializing/de-serializing them when you don't really need to do that. In one of my applications that happens to account for 80% of the execution time.

I haven't spent a lot of time with SqlAlchemy but I think an ORM that maps well to some performant database is a better approach in Python.