G protein-coupled receptors (GPCRs) are a massive and highly influential superfamily of membrane receptors that essentially control most of the physiological and signaling events in the body. When an external ligand binds to GPCRs, these receptors activate the G proteins that are associated with them. The activated G proteins in turn stimulate a host of intracellular effectors, such as adenylyl cyclase, phospholipase C, and various ion channels, thus leading to the generation of a number of secondary messengers, for example, cAMP and Ca2+. By means of these signaling pathways, GPCRs regulate a vast collection of cellular processes, which include synaptic communication, hormonal signaling, metabolic balance, immune responses, cell proliferation, etc. Their stimulation brings about a battery of structural and biochemical changes in the target cell, such as phosphorylation of the receptor, changes through posttranslational modifications, β-arrestin recruitment, and receptor internalization. All these changes serve to both control and fine-tune the intensity and duration of GPCR signaling. Being at the center of a vast network of physiological pathways, GPCRs are deeply implicated in the etiology and the development of a large spectrum of diseases, comprising neurological and psychiatric disorders, metabolic diseases, various kinds of cancer, inflammatory diseases, and cardiovascular disorders. Besides regulating the activity of individual cells, GPCR-mediated signaling cascades also facilitate the communication between cells and ensure the coordinated transmission of signals across tissues for the preservation of physiological homeostasis. If the activation of GPCRs is prolonged or sustained, it can change cellular functions by altering transcriptional activity and through epigenetic regulation; thus, these changes may either be permanent adaptive responses or may contribute to disease progression. To sum up, the enormous repertoire of signaling mechanisms controlled by GPCRs underlines their indispensable role in sustaining physiological balance as well as their implication in various disorders, thus providing the rationale for considering them as the primary targets of contemporary therapeutic research and drug development.