The mechanisms leading to diabetic cardiomyopathy and failure are complex. Eventually the pathological alterations will result in mismatch between the load applied to the heart and the energy needed for contraction, leading to mechanoenergic uncoupling. After initial insults (episodes of hyperglycemia), secondary mediators such as angiotensin II (AII), norepinephrine (NE), endothelin (ET), proinflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin 6 and IL1β (IL-6 and IL1β), in concert with oxidative stress and peroxynitrite, activate downstream effectors (e.g., PARP-1 or MMPs)], act directly on the myocardium or indirectly via changes in hemodynamic loading conditions to cause endothelial and myocardial dysfunction, cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation, and myocardial necrosis, leading eventually to heart failure. The adverse remodeling and increased peripheral resistance further aggravate heart failure. MMPs, matrix metalloproteinases; PARP-1, poly(ADP-ribose) polymerase.