The efficacy of selective endothelin (ET) receptor antagonists may be limited by a functional interaction between the ET A and ET B receptors. This interaction, also termed “cross talk”, is characterized by the dependency of the inhibition of an ET-1 response due to antagonism of one ET receptor subtype upon concomitant antagonism of the other ET receptor subtype. Although a reduction in ET A-ET B receptor cross talk would presumably increase the efficacy of selective ET receptor antagonists, an approach that accomplishes this aim is largely absent due to a lack of mechanistic understanding. Toward this goal, we evaluated the characteristics and potential dependencies of cross talk in smooth muscle. Smooth muscle was adopted as an exemplar not only because cross talk is widely reported in this tissue type, thereby allowing numerous comparisons, but also significant controversy surrounds the use of selective versus nonselective ET receptor antagonists in ET-1–related pathophysiologies involving smooth muscle. Based on this evaluation, we suggest that ET A-ET B receptor cross talk is a dynamic process directed by either or both ET receptor subtypes and expressed to varying magnitudes depending on the ET-1 and selective ET receptor antagonist concentrations, tone due to intraluminal pressure/stretch, agonists acting at receptors other than the ET A/ET B receptors, and endothelial/epithelial function. It is speculated that ET A-ET B receptor cross talk occurs through signal transduction pathways along with changes at the receptor level. Pharmacologic intervention of the signaling pathways could increase the therapeutic efficacy of ET receptor antagonists.