Calpain, calcium-activated neutral protease, stands as a unique receptor for calcium signals in biological systems; its activation leads to irreversible proteolytic processing of substrate proteins, modifying cellular situations in a manner distinct from that of reversible processes including the phosphorylation-dephosphorylation reactions. Because the enzyme participates not only in normal intracellular signal transduction cascades but also in various pathological states including ischemia, calpain research has attracted tremendous interest in wide areas of life sciences in both basic and clinical terms. This review will address the new perspectives evoked by recent discoveries since 1990. Molecular biological studies have established that calpain in fact constitutes a large family of distinct isozymes differing in structure and distribution, whereas an increasing number of reports describe physiological-pathological involvement of calpain. Another major accomplishment is the technical breakthrough allowing spatial resolution of calpain action presenting a clearer in vivo picture of how calpain acts in cells and tissues.