G protein-coupled receptors (GPCRs) are highly tractable drug targets, however, discovery for CNS disorders suffers from high attrition rates. Allosteric modulators offer the potential to fine-tune GPCR activity when and where the endogenous neurotransmitter is present. This symposium showcases research encompassing the continuum of preclinical GPCR allosteric modulator drug discovery, from molecular pharmacology and chemical biology through to in vivo models of CNS disorders and pain. Speakers will present efforts to harness new paradigms of allosteric drug action (biased signaling and light control) to avoid common pitfalls (selectivity, adverse effect liability) and enhance efficacy.