A comprehensive review of studies describing the role of G-protein coupled receptor (GPCR) behaviour contributing to metastasis in cancer, and the developments of biotherapeutic drugs towards targeting them, provides a valuable resource toward improving our understanding of the opportunities to effectively target this malignant tumour cell adaptation. Focusing on the five most common metastatic cancers of lung, breast, colorectal, melanoma, and prostate cancer, we highlight well-studied and characterised GPCRs and some less studied receptors that are also implicated in the development of metastatic cancers. Of the approximately 390 GPCRs relevant to therapeutic targeting, as many as 125 of these have been identified to play a role in promoting metastatic disease in these cancer types. GPCR signalling through the well-characterised pathways of chemokine receptors, to emerging data on signalling by orphan receptors, is integral to many aspects of the metastatic phenotype. Despite having detailed information on many receptors and their ligands, there are only thirteen approved therapeutics specifically for metastatic cancer, of which three are small molecules with the remainder including synthetic and non-synthetic peptides or monoclonal antibodies. This review will cover the existing and potential use of monoclonal antibodies, proteins and peptides, and nanobodies in targeting GPCRs for metastatic cancer therapy.