The most intensely studied members of the calpain superfamily are the mammalian ubiquitous calpain 1 and 2. They were named according to their Ca2+ requirement for activation in vitro. Calpain 1 and 2 need micro-molar and milli-molar Ca2+ concentrations, respectively, for their proteolytic activity [11,12]. They are heterodimers and consist of a distinct 80 kDa large catalytic subunit (encoded by CAPN1 and CAPN2, respectively) and a common 30 kDa small subunit (encoded by CAPNS1) that regulates calpain activity [13,14]. The catalytic subunit can be further divided into four functional domains (DI-DIV), while the small subunit comprises two domains (DV-DVI) (Figure 1) [15,16].