It is widely recognized that obesity and insulin resistance can contribute to an increased risk of coronary disease, but it has also become increasingly apparent that they may contribute directly to cardiac dysfunction even in the absence of significant coronary disease. Recently, obesity, which is frequently accompanied by insulin resistance, has been independently related to clinically diagnosed heart failure. Thus, there is renewed interest in the pathophysiology of myocardial disease related to obesity and insulin resistance, as well as in the specific cellular mechanisms by which obesity may cause detrimental cardiac structural and functional changes. Alterations in hemodynamics, plasma volume, neurohormonal status, and myocardial substrate metabolism all appear to contribute to these changes. Improving our understanding of cardiac dysfunction related to obesity and insulin resistance may provide clues for new strategies to prevent and treat this alarmingly prevalent condition.