Obesity is thought to be a major determinant in the development of cardiovascular diseases, but the mechanisms whereby enlarged adipose tissue affects vascular function remain poorly defined. Chronic inflammation is a common feature of obesity and atherosclerosis, and several inflammatory markers produced by adipose tissue have been considered as candidates that potentially favor the development of atherosclerostic lesions in humans. To identify other effective candidates, we combined bioclinical data for individuals of increasing weight with adipose tissue gene-expression profiling. This strategy led to the discovery of cathepsin S (CTSS), for which gene expression was strongly correlated with subjects' body mass index (BMI). CTSS is an elastolytic cysteine protease that has been implicated in the development of atherosclerotic lesions in both animal models and humans. In this review, we discuss the role of CTSS in obesity and atherosclerosis, and emphasize the potential mechanisms that could link the two diseases. We also position this protease as a potential therapeutic target to reduce associated cardiovascular risks in obese patients.