Cardiometabolic disorders have been shown to impair coronary microvascular functions leading to diminished cardiac performance and increased mortality. In this review, we focus on the molecular pathomechanisms of impaired endothelium-dependent and flow-induced dysregulation of coronary vasomotor tone in cardiometabolic disorders such as obesity, diabetes mellitus or hyperhomocysteinemia based on animal experiments and human studies. We also briefly summarize the relationship among key signaling mechanisms that contribute to the development of coronary dysfunctions in these disorders, which may help develop new targets for efficient cardiometabolic prevention and treatments.