Cluster of differentiation 36 (CD36), also referred to as scavenger receptor B2, has been shown to serve multiple functions in lipid metabolism, inflammatory signaling, oxidative stress, and energy reprogramming. As a scavenger receptor, CD36 interacts with various ligands, such as oxidized low-density lipoprotein (oxLDL), thrombospondin 1 (TSP-1), and fatty acid (FA), thereby activating specific downstream signaling pathways. Cardiac CD36 is mostly expressed on the surface of cardiomyocytes and endothelial cells. The pathophysiological process of diabetic cardiomyopathy (DCM) encompasses diverse metabolic abnormalities, such as enhanced transfer of cardiac myocyte sarcolemmal FA, increased levels of advanced glycation end-products, elevation in oxidative stress, impaired insulin signaling cascade, disturbance in calcium handling, and microvascular rarefaction which are closely related to CD36 signaling. This review presents a summary of the CD36 signaling pathway that acts mainly as a long-chain FA transporter in cardiac myocytes and functions as a receptor to bind to numerous ligands in endothelial cells. Finally, we summarize the recent basic research and clinical findings regarding CD36 signaling in DCM, suggesting a promising strategy to treat this condition.