The G protein-coupled receptors (GPCRs) comprise a diverse superfamily of integral membrane proteins that communicate changes in the extracellular environment to the cell interior. In order to make haploid yeast strains useful as a host for genetic analysis of heterologous GPCR function or in screening for novel agonist or antagonist compounds, the pheromone response pathway must be modified to allow the host cells to exhibit a growth response dependent on agonist activation. The yeast cells undergo desensitization or adaptation in response to chronic stimulation of the pheromone response pathway. The primary adaptation mechanism is mediated by the yeast RGS protein, Sst2. When expressing GPCRs in yeast for the purpose of agonist and antagonist highthroughput screening or structure-function analysis, a pharmacological profile is a critical step for any heterologous expression system. A practical use of the yeast expression system is for the discovery of novel agonists and antagonists by high-throughput screening of chemical and natural products libraries.