Cysteine cathepsins are proteolytic enzymes that play an integral role in tissue destructive diseasessuch as atherosclerosis, cancer and osteoporosis by degrading extracellular matrix including collagen, gelatin andelastin. As such, pharmaceutical inhibitors have been developed to target them, however, all but one of the 16drugs that has made it to phase II clinical trials has been discontinued due to side effects. There is a need tounderstand why these well-designed inhibitors are not working in vivo. Previous research has shown that somecathepsins will preferentially degrade other cathepsins, even in the presence of target substrate, a behavior knownas cathepsin cannibalism. Determining cathepsin cannibalism directionality and substrate preferences will beginto unravel the complex proteolytic network dynamics of these enzymes, and provide insight into their levels invivo that complicate pharmaceutical dosing and inhibition strategies