The superfamily of G-protein-coupled receptors (GPCRs) is one of the largest mammalian protein families. It is involved in signal transduction and participates in the regulation of normal physiological function and pathological progression of a range of diseases. Recent studies have demonstrated that many aberrant GPCRs and their ligands are associated with tumorigenesis, angiogenesis and metastasis, which provides promising opportunities for drug discovery for cancer prevention and treatment. It is necessary to search for drug targets such as ligands of unknown GPCRs and better modulators of known GPCRs using high throughput screening approaches. Here, we review recent research advances in the identification of novel GPCRs and their protein interactions.