Diabetes is a risk factor for coronary atherosclerosis, myocardial infarction, and ischemic cardiomyopathy. Insulin resistance is associated with left ventricular (LV) hypertrophy and hypertensive cardiomyopathy. Even in the absence of coronary artery disease or hypertension, "diabetic cardiomyopathy" can develop because of myocardial autonomic dysfunction or impaired coronary flow reserve. The relationship between insulin resistance and cardiomyopathy is bidirectional. Systemic and myocardial glucose uptake is compromised in heart failure independent of etiology. These abnormalities are associated with cellular deficits of insulin signaling. Insulin resistance in heart failure can be detrimental, because transcriptional shifts in metabolic gene expression favor glucose over fat as a substrate for high-energy phosphate production. Although preexisting diabetes accelerates this process of "metabolic death," insulin resistance can also develop secondary to cardiomyopathy-associated overabundance of neurohormones and cytokines. Insulin resistance and fatty acid excess are potential therapeutic targets in heart failure, striving for efficient myocardial substrate utilization. Peroxisome proliferator activator receptor gamma (PPARgamma) agonists are antidiabetic agents with antilipemic and insulin-sensitizing activity. Experimental studies suggest salutary effects in limiting infarct size, attenuating myocardial reperfusion injury, inhibiting hypertrophic signaling and vascular antiinflammatory actions through cytokine inhibition. However, clinical applicability in diabetic patients experiencing heart failure has been hampered because of increased edema and even fewer reports of exacerbation associated with these compounds. Evidence to date argues for peripheral mechanisms of edema unrelated to central hemodynamics. Nevertheless, they are currently contraindicated in New York Heart Association (NYHA) III-IV patients, particularly in combination with insulin. Investigations are underway to decipher mechanisms, risks, and benefits of PPARgamma agonists, as well as the role of the structurally related PPARalpha receptor on cardiovascular metabolism and function.