Catecholamines including dopamine (DA) and norepinephrine (NE) are widely distributed in the body and exert extensive physiological functions by serving as neurotransmitters or neuromodulators. Alterations in the level of these two catecholamines underlie many neurological and psychiatric disorders. The pharmacology of both DA and NE including their individual receptors, signaling mechanisms, agonists and antagonists has been extensively studied. Whereas the traditional idea is that neurotransmitters specifically interact with their receptors, there is compelling evidence indicating that DA and NE exert biological actions by activating the receptors of other family in a variety of regions. Here, I review the experimental evidence showing cross activation of each other’s receptors by these two catecholamines. This promiscuous interaction may represent a novel way for catecholamines to exert their functions.