By virtue of their specific interactions with extracellular ligands, cell surface receptors can transduce signals, carry out endocytosis and other forms of transport, and mediate the adhesion of cells to their substrata or to other cells. While it has generally been assumed that physiologic activities and appropriate responses to pathophysiologic states require that only one ligand be recognized by its cognate receptor, this “one ligand–one receptor” notion is now in need of extensive revision. This Perspective series focuses on several striking examples of multiligand receptors, molecules that interact specifically with classes of structurally related ligands or even with several structurally and functionally dissimilar ligands. Such broad specificity raises intriguing problems for biological regulation that do not arise with classical, monospecific receptors. From the vantage point of the economy of host gene expression, it is expeditious to have a single protein subserve multiple roles, and for this reason, some authors have speculated that these proteins arose early in molecular evolution. However, the various functions are probably subject to precise regulation to avoid the possibility that a range of stimuli all activate a single cellular response, which might have disastrous consequences for the cell’s ability to adapt to environmental challenges. How can one make sense of these types of receptor-ligand interactions? What basic principles have emerged from their study?