G-protein-coupled receptors (GPCRs) constitute the largest but the most divergent class of cell surface proteins. Although they are thought to share a common 3D-structure composed of seven transmembrane helical domains, they can be activated by extracellular signals as diverse as light, peptides, proteins, lipids, organic odorants, taste molecules, nucleotides or nucleosides. They are involved in an extraordinarily large number of physiological functions and are therefore potential drug targets for many human diseases. During the last decade various GPCRs have been successfully expressed in S. cerevisiae. Yeast is an attractive expression system because it offers the genetic engineering tools typical of a microorganism while possessing an eukaryotic type of secretory pathway and post-translational machinery. This host is particularly attractive for in-vivo manipulation of these receptors due to the high homology between the yeast pheromone signaling pathway and that of mammalian GPCRs. When expressed in yeast, mammalian GPCRs have been shown to couple functionally to either the endogenous yeast Galpha (Gpa1), or co-expressed mammalian Galpha subunits (wild-type or chimeric), and are characterized by a similar pharmacology in response to agonists or antagonists as in native cells. Heterologous expression of wild type or mutant GPCRs in S. cerevisiae allows a rapid assessment of their ability to detect and transduce extracellular stimulations, through the use of a reporter system. Furthermore, this approach is amenable to high-throughput screening of new drugs, which would provide a determinant advantage in the field of therapeutic research, and also for investigation of the still unknown ligands of orphan receptors. This review will focus on the latest developments of yeast-based technology to screen for potential GPCR agonists/antagonists.