An almost exponential development has occurred within the last five years in the area of non-peptide ligands for G protein-coupled 7TM receptors. For most of the major peptide targets a number of highly selective high affinity antagonists are today available and recently the first non-peptide agonists have started to appear as well. Mutational mapping of binding sites, which has reached a reasonably detailed level especially in the tachykinin and angiotensin systems, indicate that the peptide agonists are primarily interacting with residues located in the exterior part of the main ligand binding pocket, i.e. between the loops and the outermost segments of the trans-membrane helices. Some peptides may reach down between the helices, however, a peptide as substance P does not appear to interact at all with residues corresponding to the deeply located presumed binding site for monoaminex. In contrast, presumed interaction points for non-peptide antagonists are predominantly found in the deep part of the main ligand binding pocket between the transmembrane segments. In general, it has been unexpectedly difficult and in some well characterized cases, even impossible to identify point mutations which affect both peptide agonists and non-peptide antagonists - while multiple mutations affect either one or the other ligand These surprising observations may be explained by an allosteric receptor model where the ligands exert their effect merely by selecting and stabilizing preformed receptor conformations and thereby shifting the equilibrium towards either an active or an inactive form. In this receptor model there is no requirement for a common 'lock' for all agonists and it does not demand an overlap in binding site between competitive ligands - they can compete by binding in a mutually exclusive fashion, thus being allosteric competitive in contrast to isosteric classical competitive ligands.