#1 In python specifically, we do not have proper closure and no anonymous blocks, this makes operating it tedious as the definition of the logic for a callback is always somewhere else from where the callback is setup.

#2 In any language supporting proper closures (javascript for instance, hello node.js) excessive, nested use of callback based frameworks leads to the phenomenon of the pyramid of death, whereas you keep nesting closures and you have to keep them all in one place because each depends on its outer scope.

I intently dislike twisted and node.js for these very reasons. I've written my own little framework based entirely on greenlets in python, which is delightful and easy to use and entirely avoids both dislocality of action and the pyramid of death.