Guanine nucleotide-binding protein-coupled receptors may attain an active conformation in the absence of agonist by spontaneous isomerization and thus yield constitutive, agonist-independent, activity. This has mainly been demonstrated for isolated membranes and recombinant wild-type receptors, and mutant receptors. They generally show remarkable increases in the sensitivity of a biological response. The location of activating mutations both within a single receptor and across receptors is widespread, with changes reported in the seven-transmembrane domains, the second and third intracellular loop. For most of these receptors, examples of ligands defined as inverse agonists have been documented. Regulation of these receptors by inverse agonists opposite to that observed by agonists, and the therapeutic potential of inverse agonists is underlined.