Is it better to choose recommenders by discipline or by familiarity? I'm going to be applying for postdocs in the immediate future in either physics or pure mathematics (preferably the latter, though my focus won't change). Assume for the sake of argument the following two letters are strong: (1) my PhD advisor (a physicist by training) and (2) a lesser-known mathematician whom I've been collaborating with recently but haven't produced anything yet. Now, suppose I need a third letter. 

My interests have often brought me into collaboration with people in a different disciplines. Do I choose the third letter based upon how well the third person knows me or based upon the discipline of the job I'm applying for?
Ideally you want someone who is well known to people on the hiring committee.

It sounds like you already have letters from two people who are very familiar with your work.  If you can get a STRONG letter from a "big shot" in the field (math?), you should go for it.  That person doesn't need to know you very well, but he/she should be able to put your work in context and explain why it is important/interesting.