Calpains are members of a large family of Ca2+-dependent proteolytic enzymes. Some are tissue-specific; others are ubiquitous. Poised to digest numerous intracellular proteins, their potential to cause or contribute to disease is considerable. This review outlines the structure and function of calpains and their involvement in a type of muscular dystrophy, type 2 diabetes, cataracts, and Alzheimer's disease.