Calpains are nonlysosomal, calcium-activated intracellular cysteine proteases that mediate specific Ca2+-dependent processes including cell fusion, mitosis and meiosis. Calpains are heterodimers of a small regulatory subunit and one of three large catalytic subunits, designated Calpain 1, Calpain 2 and Calpain p94. Calpain 1 is an intracellular calcium-dependent protease that cleaves cytoskeletal and submembranous proteins. Calpain-1 co-localizes with human leukocyte antigen-DR (HLA-DR) on activated microglia in the aging brain. Cal-pain influences the process of spermatogenesis and the events preceding fertilization, such as the acrosome reaction. Calpastatin regulates Calpain by inhibiting both the proteolytic activity of Calpain and its binding to membranes. Calpastatin exists in two types, tissue type and erythrocyte type, resulting from both alternative splicing and proteolytic processing.