Cysteine cathepsins (11 in humans) are mostly located in the acidic compartments of cells. They have been known for decades to be involved in intracellular protein degradation as housekeeping proteases. However, the discovery of new cathepsins, including cathepsins K, V and F, has provided strong evidence that they also participate in specific biological events. This review focuses on the current knowledge of cathepsin K, the major bone cysteine protease, which is a drug target of clinical interest. Nevertheless, we will not discuss recent developments in cathepsin K inhibitor design since they have been extensively detailed elsewhere. We will cover features of cathepsin K structure, cellular and tissue distribution, substrate specificity, and regulation (pH, propeptide, glycosaminoglycans, oxidants), and its putative roles in physiological or pathophysiological processes. Finally, we will review the kinetic data of its inhibition by natural endogenous inhibitors (stefin B, cystatin C, H- and L-kininogens).