The relevance of PPARγ (peroxisome-proliferator-activated receptor γ) as an important therapeutic target for the treatment of diabetes arises from its hypoglycaemic effects in diabetic patients and also from the critical role in the regulation of cardiovascular functions. From a clinical perspective, differences between current FDA (Food and Drug Administration)-approved PPARγ drugs have been observed in terms of atherosclerosis and cardiac and stroke events. The adverse effects of PPARγ-specific treatments that hamper their cardiovascular protective roles, affirm the strong need to evaluate the efficacy of the current drugs. Therefore active research is directed towards high-throughput screening and pharmacological testing of a plethora of newly identified natural or synthetic compounds. In the present review we describe the rationale behind drug design strategies targeting PPARγ, based on current knowledge regarding the effects of such drugs in experimental animal models, as well as in clinical practice. Regarding endogenous PPARγ ligands, several fatty acid derivatives bind PPARγ with different affinities, although the physiological relevance of these interactions is not always evident. Recently, NO-derived unsaturated fatty acids were found to be potent agonists of PPARs, with preferential affinity for PPARγ, compared with oxidized fatty acid derivatives. Nitroalkenes exert important bioactivities of relevance for the cardiovascular system including anti-inflammatory and antiplatelet actions, and are important mediators of vascular tone. A new generation of insulin sensitizers with PPARγ function for the treatment of diabetes may serve to limit patients from the increased cardiovascular burden of this disease.