Atherosclerosis-based vascular disease is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathological events, the discovery of cysteine protease cathepsins, such as cathepsins K, S, L, and B, and cystatin C, and their tissue distribution has suggested that at least some of them participate in cardiovascular disease. Studies on vascular cells have shown that atherosclerosis-associated inflammatory cytokines augment cysteinyl cathepsin expression and activity. Novel insight into cathepsin functions has been made possible by the generation and in-depth analysis of knockout and transgenic mice. These studies have provided direct evidence implicating cathepsins in atherosclerosis-based vascular disease through the activation, liberation, and modification of angiogenic growth factors, cytokines, and proteases associated with lipid metabolism, cell events (migration, invasion, proliferation, and apoptosis), angiogenesis, and matrix protein remodeling. Furthermore, evaluation of the feasibility of cathepsins as a diagnostic tool has revealed that the serum cathepsins S and L and the endogenous inhibitor cystatin C hold promise as biomarkers of coronary artery disease and aneurysm formation. The goal of this review is to summarize the available information regarding the mechanistic contributions of cathepsins in atherosclerosis-based vascular disease.