Calpain, an inactive proenzyme, translocates from the cytosol to the membrane upon binding calcium, and is activated at the membrane in the presence of calcium and PIP2. Activated calpain is very unstable and presumably used only once. Thus the primary targets of calpain are considered to be membrane or membrane-associated proteins. Activation of protein kinase C (PKC) occurs concomitantly with calpain at the membrane. Calpain hydrolyzes only the active PKC species leading to downregulation. Calpain participates in the transcriptional regulation by controlling the levels of transcription factors, c-Jun and c-Fos. The calpain gene is a TPA-responsive gene and its expression is stimulated by activation of PKC. Modulation of cellular signal transduction by controlling the levels of the component proteins, such as PKC, c-Jun and c-Fos is one of the important physiological roles of calpain.