There are some 850 human G protein-coupled receptors (GPCRs) currently known (http://bioinformatics2. biol. uoa. gr), making this the most abundant family of well-characterized protein receptors on the cell surface. Their function is to mediate signal transduction across the cell membrane, and they are so named because they couple intracellularly with G proteins, although it is now known that they also couple other types of intracellular proteins as well. 1-5 About 60% of known GPCRs are sensory and olfactory receptors that mediate vision, taste, smell, and so forth, while the other∼ 300 known GPCRs respond to extracellular stimuli like protein and peptide hormones, amino acids, biogenic amines, lipids. 6, 7 Consequently, GPCR proteins have become just about the most intensively studied targets for drug development, accounting for∼ 30% of pharmaceuticals used in man and∼ 10% of global pharmaceutical sales. 8-10 Yet, such licensed human pharmaceuticals only target∼ 30 (4%) of the known GPCRs, and include R1 antagonists (eg, doxazosin, terazosin), β-agonists (salmeterol, salbutamol) and antagonists (metoprolol, atenolol), histamine antagonists (eg, loratadine, fexofenadine, ranitidine, famotidine, cetirizine, cimetidine), 5-HT agonists/antagonists (eg, olanzapine, respiradone, sumatriptan, ondansetron, buspirone, cisapride), and GABA agonists (gabapentin). 8, 9 Several hundred other human GPCRs are known to be activated by extracellular protein or peptide ligands, 11 but only a few of these receptors are currently targeted by marketed drugs (Table 1). 8 Such drugs include angiotensin AT1 antagonists (losartan, valsartan), endothelin antagonist (bosentan), LHRH agonists (leuprolide, goserelin), NK1 antagonist (aprepitant), oxytocin OTR antagonist (atisoban), somatostatin SSTR agonists (SRIF-14, octreotide, lanreotide), and vasopressin antagonists (conivaptan). Clearly, peptide/protein-activated GPCRs represent a large, promising, and still under-developed source of new pharmaceutical targets for treating human diseases or medical conditions. This perspective review describes a necessarily limited selection of key small molecule nonpeptidic agonists and antagonists that have been identified to date as regulators of peptideactivated GPCRs, and outlines some of their pharmacological properties. It provides a cross section of scientific literature up to the end of 2005, in some cases through early 2006, without attempting to describe compound syntheses or the extensive patent literature.