Proteases play diverse roles in a variety of essential biological processes, both as non-specific catalysts of protein degradation and as highly specific agents that control physiologic events. Here, we review the mechanisms of substrate specificity employed by serine proteases and focus our discussion on coagulation proteases. We dissect the interplay between active site and exosite specificity and how substrate recognition is regulated allosterically by Na+ binding. We also draw attention to a functional polarity that exists in the serine protease fold, which sheds light on the structural linkages between the active site and exosites.