The most important goal in the treatment of patients with diabetes is to prevent the risk for cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of anti-diabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal, and reducing hepatic glucose output. TZDs including pioglitazone, roglitazone and troglitazone, by activating nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, toglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics is an important tool in further understand inter-subject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.