A dramatic rise in the prevalence of insulin resistance has been paralleled by increasing dietary consumption of sugar. The use of added sweeteners containing fructose (sucrose and high-fructose corn syrup) has increased by 25% over the past 3 decades. High fructose intake has the potential to adversely influence systemic and cellular metabolism via insulin resistance and glycolytic dysregulation. As a tissue that is both insulin sensitive and glycolysis dependent, the heart may be especially vulnerable to fructose over-consumption. In this review, experimental studies of elevated dietary sugar intake are evaluated, including sucrose and fructose dietary manipulation models. The possible role of the GLUT5 transporter as a mediator of cardiomyocyte fructose uptake is considered. The impact of dietary sucrose and fructose on cardiac insulin-dependent signaling in the context of perturbed systemic metabolic response is detailed. Myocardial dysfunction, modified growth, and oxidative stress responses associated with high dietary sugar intake are discussed. Finally, the involvement of the renin–angiotensin system in mediating fructose cardiopathology is considered. This review highlights the importance of obtaining new mechanistic data that can contribute to a more developed understanding of how high sugar intake directly contributes to structural and functional cardiomyopathy.