Receptors are at the heart of how a molecule transmits a signal to a cell. Two receptor classes for endothelin (ET) are recognized, the ET(A) and ET(B) receptors. Intriguing questions have arisen in the field of ET receptor pharmacology, physiology, and function. For example, a host of pharmacological studies support the interaction of the ET(A) and ET(B) receptor in tissues (veins, arteries, bronchus, arterioles, esophagus), but yet few have been able to demonstrate direct ET(A)/ET(B) receptor interaction. Have we modeled this interaction wrong? Do we have a truly selective ET(A) receptor agonist such that we could selectively stimulate this important receptor? What can we learn from the recent phylogenic studies of the ET receptor family? Have we adequately addressed the number of biological molecules with which ET can interact to exert a biological effect? Recent mass spectrometry studies in our laboratory suggest that ET-1 interacts with other hereto unrecognized proteins. Biased ligands (ligands at the same receptor that elicit distinct signaling responses) have been discovered for other receptors. Do these exist for ET receptors and can we take advantage of this possibility in drug design? These and other questions will be posed in this minireview on topics on ET receptors.