Recent very rapid developments in genome and EST projects have identified an increasing number of gene products homologous to those that were previously identified by other methods. Calpain is no exception. At the time this review is written, 83 genes from 23 living organisms have been identified in the database to encode amino acid sequences showing significant similarities to the protease domain of “conventional” calpain, which was first purified as a homogeneous protein in 1978. Progress in genome/ EST projects has occurred so quickly that there seems to be some confusion as to the identity of each calpain molecule. This review will attempt to clarify all calpain homo-logues, to describe the common and differing features of calpain homologues in terms of structure-function relationship, and to discuss the evolutionary process of calpain.