G-protein-coupled receptors (GPCRs) are the largest family of receptors in humans. GPCRs are seven-transmembrane receptors that are activated by the binding of a ligand to the extracellular domain. In addition to the endogenous ligands, auto-antibodies (aab) can also bind to the GPCRs. They can activate different and specific cellular pathways which contribute to various diseases. In this review, the authors summarize the knowledge about antibodies targeting GPCRs and their effects and relevance in the pathogenesis of various diseases and their use in clinical diagnostics. We highlight the role of different activating anti-GPCR aab in solid organ transplantations, stem cell transplantations, systemic sclerosis, preeclampsia, chronic fatigue syndrome, cardiovascular diseases, Alzheimer’s disease, and cancer.