Cathepsins are a group of cysteine proteases that are involved in proteolysis in lysosome and control various signaling pathways in cells. Among different cathepsins, CatK has been of high interest as it occurs abundantly in osteoclasts and plays an important role in resorption and remodeling of bones. As such it has been a drug target for the treatment of osteoporosis, a condition in which bones decrease their density significantly and become fragile. Several covalent inhibitors were designed to target CatK for the treatment of osteoporosis but have been discontinued owing to their side effects. Balicatib showed great selectivity for CatK with respect to other cathepsins 241 but was discontinued after its Phase II clinical studies as it led to morphea-like skin lesions in some patients. Among many covalent inhibitors of CatK, odanacatib reached phase-III trials. Odanacatib possesses a nitrile group that reacts with Cys25 of CatK to form an iminothioester adduct ; unlike other CatK inhibitors, odanacatib does not accumulate in lysosomes, reducing its inhibition of other cathepsins and thus its side effects. Although odanacatib was efficient in increasing bone mineral density and reducing hip or vertebrae fractures, its phase III trial was prematurely terminated on the grounds that it increased the likelihood of cardiovascular complications such as stroke in patients. A CatK inhibitor that is currently in the phase II clinical trial stage for osteoporosis and osteoarthritis is MIV-711. Among other cathepsins, CatS has been found to play a unique role in mediating the immune response in dendritic and B cells. Hence inhibition of CatS can be useful for combatting hyperactivation of immune systems against host antigens in several autoimmune diseases such as rheumatoid arthritis, bronchial asthma etc. Although no CatS specific covalent inhibitor has been approved by the US FDA, several compounds have been discovered and investigated in vitro and in vivo to inhibit CatS specifically, such as Balicatib; Odanacatib; JPM-OEt; and JPM-565. 242, 252-258