Heterotrimeric G-protein-coupled receptors (GPCRs) represent a large protein family responsible for mediating extracellular to intracellular signaling within a broad range of physiological contexts. Various conventional models have been used to describe their interactions with ligands and G-proteins. In recent years, however, numerous novel ligand-receptor interactions not adequately addressed by classical receptor theory have been recognized. In addition to traditional orthosteric ligands, many GPCRs can bind allosteric ligands that modulate receptor activity by interacting with distinct or overlapping receptor sites. Such ligands include positive allosteric modulators, which have become the focus of pharmaceutical drug discovery programs and have gained the attention of a growing body of basic and translational researchers within the academic community. Here, we review the fundamental aspects of allosteric GPCR modulation by small-molecule ligands, with particular focus on the emerging position of positive allosteric modulators in modern drug discovery.