Desquamation or cell shedding in mammalian skin is known to involve serine proteases, aspartic proteases and glycosidases. In addition, evidence continues to accumulate that papain-like cysteine proteases and an inhibitor cystatin M/E largely confined to the cutaneous epithelia also play key roles in the process. This involves the complete proteolysis of cell adhesive structures of the stratum corneum, the corneodesmosomes and notably of the desmogleins. Continual cell replacement in the epidermis is the result of the balance between the loss of the outer squames and mitosis of the cells in the basal cell layer. This article provides a brief account of the salient features of the characteristics and catalytic mechanism of cysteine proteases, followed by a discussion of the relevant epidermal biology. The proteases include the asparaginyl endopeptidase legumain, which exerts a strict specificity for the hydrolysis of asparaginyl bonds, cathepsin-V and cathepsin-L. The control of these enzymes by cystatin M/E regulates the processing of transglutaminases and is crucial in the biochemical pathway responsible for regulating the cross-linking and desquamation of the stratum corneum. In addition, caspase-14 has now been shown to play a major part in epidermal maturation. Uncontrolled proteolytic activity leads to abnormal hair follicle formation and deleterious effects on the skin barrier function.