Over the past three decades, at least 10 hormones secreted by the enteroendocrine cells have been discovered, which directly affect the cardiovascular system through their innate receptors expressed in the heart and blood vessels or through a neural mechanism. Glucagon-like peptide-1 (GLP-1), an important incretin, is perhaps best studied of these gut-derived hormones with important cardiovascular effects. In this review, I have discussed the mechanism of GLP-1 release from the enteroendocrine L-cells and its physiological effects on the cardiovascular system. Current evidence suggests that GLP-1 has positive inotropic and chronotropic effects on the heart and may be important in preserving left ventricular structure and function by direct and indirect mechanisms. The direct effects of GLP-1 in the heart may be mediated through GLP-1R expressed in atria as well as arteries and arterioles in the left ventricle and mainly involve in the activation of multiple pro-survival kinases and enhanced energy utilization. There is also good evidence to support the involvement of a second, yet to be identified, GLP-1 receptor. Further, GLP-1(9-36)amide, which was previously thought to be the inactive metabolite of the active GLP-1(7-36)amide, may also have direct cardioprotective effects. GLP-1's action on GLP-1R expressed in the central nervous system, kidney, vasculature and the pancreas may indirectly contribute to its cardioprotective effects.