Calpain is a conserved family of calcium-dependent, cytosolic, neutral cysteine proteases. The best characterized members of the family are the ubiquitously expressed calpain 1 and calpain 2. They perform controlled proteolysis of their target proteins. The regulation of these enzymes includes autolysis, calcium, phosphorylation as a posttranslational modification, and binding of calpastatin, phospholipids or activator proteins, respectively. Calpain are implicated in many physiological and pathological processes. They have significant role in the cell proliferation, differentiation and migration in a variety of mammalian cell types, contributing to the development of angiogenesis, vascular remodeling, and cancer. Therefore the knowledge of the precise mechanism of calpain signaling could provide therapeutic approaches in these processes.