Despite many advances in cardiology, atherosclerosis remains a major medical problem. This is especially the case for individuals with insulin resistance and type 2 diabetes mellitus. Atherosclerotic lesions can develop as early as the second decade of life and progress into clinical disease over time. Atherosclerosis is a complex disorder, involving many cell types and circulating mediators and resulting in an inflammatory state. The control of transcription of inflammatory mediators via ligands for peroxisome proliferator-activated receptor-gamma, such as thiazolidinediones (TZDs), has been raised as a possible mechanism for improving atherosclerosis. Results of studies performed in vitro and in animal models suggest that TZDs may increase cholesterol efflux from macrophages, decrease cytokine expression, and limit chemokine levels. Such effects may underlie the decreases in atherosclerosis seen in mouse models of atherosclerosis after TZD treatment. The direct actions of the TZDs on atherosclerosis may couple with their effects on metabolic parameters through increased insulin sensitivity. Ongoing clinical trials evaluating cardiovascular end points with TZD therapy should provide insight into these possibilities.