Diabetic cardiomyopathy is a heart disease in diabetic patients, identified as ventricular dysfunction in the absence of coronary artery disease and hypertension. The molecular mechanisms underlying diabetic cardiomyopathy are still poorly understood. The protein and lipid kinase phosphoinositide 3-kinases (PI3Ks) have been suggested to regulate cardiac injury during diabetes. In this review, we will summarize the role of different PI3K isoforms and of their downstream signaling in the pathogenesis of diabetic cardiomyopathy, including the regulation of cardiac metabolism, contractility, hypertrophy, myocardial cell death, and inflammation.