Identification of natural ligands for orphan G-protein-coupled receptors will help expand the boundaries of physiology and pharmacology. Powerful approaches are needed that can pair biologically active ligands with their corresponding receptors. Many attempts have been made to set up universal screening schemes such that receptor activation by its cognate ligand is transduced into a common intracellular signal that is amenable to high-throughput screening analysis. One possibility that achieves such a ‘universal assay' takes advantage of the promiscuous nature of the G-protein subunit Gα₁₆. However, a truly critical look at Gα₁₆ is still required. In this article, the strengths, weaknesses, problems and pitfalls that are associated with the use of Gα₁₆ will be discussed, and suggestions of how problems might be overcome with an optimized universal G-protein system will be proposed.