I think that one of the major drawbacks of smalltalk is its 80's implementation which offers 0 (zero) modularity. A smalltalk image is a universe, which contains everything. It can't be split on parts, you can't manage these parts to load/unload on demand. Everything is tightly welded together and sometimes, even if you want to get rid of some stuff - its very hard to do. Its like a painting ink - once you stepped into it once - you start leaving footprints everywhere. Its very good from one side, but not always: for a people working in contaminated areas, they need to pass a clean-up procedures to reduce the risk of bringing unwanted stuff into that environment. In smalltalk there is no such contaminated areas - you free to go everywhere and leave your footprints. Who cares? :) This is the problem: if people don't have a discipline and leaving stuff everywhere they think it good to be, then at the end we got a complete mess, no structure, no organization, just a half-working pieces spreaded across many places.
Also, even if organized well, projects can't grow bigger than certain amount, and at some point they become unmanageable, simply because no single man can hold so much information in his head to understand it and make some progress with it. At some point, you have to split your project on separate parts and delegate your work to other people. And also, make sure that these parts can evolve more or less independently. This is where fun begins: a smalltalk inherent implementation lacks modularity and offers nothing to you how to break things apart without losing consistency. Instead, it makes you addict in using globals everywhere and be careless about future :)
Another analogue: kids playing with lego puzzle. One kid puts one piece on top of another, then second puts some more pieces on top of it, and so on, then another kid came and realizes that if he replace the piece inside a construction it would be much more elegant. But at first attempt when he tries that, he breaks the whole construction :)
I hoping this will change in near future. Smalltalk syntax is the simplest and most powerful syntax i met.