Class C G protein-coupled receptors (GPCRs) recognise diverse extracellular stimuli and are highly tractable drug targets for a host of different psychiatric, neurological and metabolic disorders. Discovery efforts focussed on allosteric modulators for Class C GPCRs have been highly fruitful, with diverse chemotypes identified for multiple Class C members. Indeed, a positive allosteric modulator of the calcium-sensing receptor, cinacalcet, was one of the first GPCR allosteric ligands to enter the clinic. Despite this success, allosteric modulator discovery and development remains challenging. In particular, the prevalence of probe dependence and biased pharmacology (both agonism and modulation) adds considerable complexity. Recent studies have yielded new insights into the structural basis for allosteric interactions at Class C GPCRs. This information coupled with rigorous analytical approaches has increased our understanding of the rich molecular pharmacology and biology for Class C GPCRs.