G-protein coupled receptors (GPCRs) have long been at the center of investigations of the neurobiology of depression and mood disorders. Different facets of GPCR signalling pathways, including those controlling monoaminergic and neuropeptidergic hormonal systems are believed to be dysregulated in major depressive and bipolar disorders. Although these receptors are key molecular targets for a variety of therapeutic agents and continue to be the focus of intense pharmaceutical development, the molecular mechanisms activated by these GPCRs and underpin the pathological basis of mood disorders remain poorly understood. This review will discuss some of the emerging regulatory mechanisms of GPCR signaling in the central nervous system (CNS) involving protein-protein interactions, downstream effectors and cross-talk with other signaling molecules and their potential involvement in the neurobiology of psychiatric disease.