Approximately 1% of the genome of higher organisms encodes seven-transmembrane (7TM) G-protein-coupled receptors, which control an extensive range of physiological processes and represent drug targets for nearly half of all drugs that are prescribed currently. To date, most drugs that target 7TM receptors interact via the same domain as the endogenous agonist, called the orthosteric site. However, the advent of functional screening assays has greatly increased the number of allosteric ligands identified. Such ligands bind to topographically distinct sites on 7TM receptors. In addition to modulating the affinity of orthosteric ligands, allosteric ligands can also alter the efficacy of orthosteric ligands and activate 7TM receptors in their own right. In this article, we briefly review the current status of putative allosteric agonists of 7TM receptors, and discuss the promises and challenges that this class of ligand might pose for pharmacologists and the drug-discovery industry.