With the recently completed sequencing and annotation of the human genome, it has become clear that a significant portion of the genome encodes signal-transducing molecules including receptors, protein kinases, ion channels, transporters and coupling proteins. This review focuses on membrane-localized receptors, which represent the largest single group of signal-transducing molecules. Indeed, one can estimate that nearly 10% of the human genome encodes membrane-localized receptors (e.g. G-protein coupled receptors, ligand-gated ion channels and transporters). We have defined that portion of the human genome that encodes 'receptors' the receptorome. In this article, we will demonstrate how the massively parallel screening of the receptorome provides a facile and under-utilized screening platform for drug discovery. Using case studies, we will show how receptorome-based screening elucidates the mechanisms responsible for serious side-effects of both approved and investigational medications. Additionally, we will provide evidence that receptorome-based screening provides insights into novel therapeutic indications of approved medications and serves to validate targets for therapeutic drug discovery.