The prohormone convertases (PC) 1/3 and 2 are calcium-activated eukaryotic subtilisins with low pH optima which accomplish the limited proteolysis of peptide hormone precursors within neurons and endocrine cells. In this lecture, we review the biochemistry, regulation, and roles of PC1/3 and 2 in disease, with an emphasis on the work published in the last 10 years. In the 20 years since their discovery, a great deal has been learned about their localization and cellular functions. Both PCs share the same four domains: the propeptides perform important roles in controlling activation and...