Calpain is an intracellular Ca2D-dependent cysteine protease (EC 3.4. 22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2D-activated neutral protease) as well as CASF, CDP, KAF, etc. until 1990. Calpains are found in almost all eukaryotes and a few bacteria, but not in archaebacteria. Calpains have a limited proteolytic activity, and function to transform or modulate their substrates’ structures and activities; they are therefore called,“modulator proteases.” In the human genome, 15 genes—CAPN1, CAPN2, etc.—encode a calpainlike protease domain. Their products are calpain homologs with divergent structures and various combinations of functional domains, including Ca2D-binding and microtubule-interaction domains. Genetic studies have linked calpain deficiencies to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy, and diabetes. This review of the study of calpains focuses especially on recent findings about their structure–function relationships. These discoveries have been greatly aided by the development of 3D structural studies and genetic models.