A link between excess dietary sugar and cardiac disease is clearly evident and has been largely attributed to systemic metabolic dysregulation. Now a new paradigm is emerging, and a compelling case can be made that fructose-associated heart injury may be attributed to the direct actions of fructose on cardiomyocytes. Plasma and cardiac fructose levels are elevated in patients with diabetes, and evidence suggests that some unique properties of fructose (vs. glucose) have specific cardiomyocyte consequences. Investigations to date have demonstrated that cardiomyocytes have the capacity to transport and utilize fructose and express all of the necessary proteins for fructose metabolism. When dietary fructose intake is elevated and myocardial glucose uptake compromised by insulin resistance, increased cardiomyocyte fructose flux represents a hazard involving unregulated glycolysis and oxidative stress. The high reactivity of fructose supports the contention that fructose accelerates subcellular hexose sugar-related protein modifications, such as O-GlcNAcylation and advanced glycation end product formation. Exciting recent discoveries link heart failure to induction of the specific high-affinity fructose-metabolizing enzyme, fructokinase, in an experimental setting. In this Perspective, we review key recent findings to synthesize a novel view of fructose as a cardiopathogenic agent in diabetes and to identify important knowledge gaps for urgent research focus.