Many β-adrenoceptor agonists and antagonists including several clinically used drugs have been reported to also exhibit binding to α-adrenoceptors. Such promiscuity within the adrenoceptor family appears to occur more often than off-target effects of drugs in general. It should not be considered surprising based on the amino acid homology among the nine adrenoceptor subtypes including the counter-ions for binding the endogenous catecholamines. When β-adrenoceptor ligands also bind to α-adrenoceptors, they almost always act as antagonists, regardless of being agonists or antagonists at the β-adrenoceptor. The α-adrenoceptor affinity of β-adrenoceptor ligands in most cases is at least one, and often more log units lower than at their cognate receptor. Consistent evidence from multiple investigators indicates that β-adrenoceptor ligands relatively have the highest affinity for α- and lowest for α-adrenoceptors. While promiscuity among adrenoceptor subtypes causes misleading interpretation of experimental in vitro data, it is proposed based on the law of mass action that α-adrenoceptor binding of β-adrenoceptor ligands rarely contributes to the clinical profile of such drugs, particularly if they are agonists at the β-adrenoceptor.