Membrane protein-protein interactions are important for regulation, targeting, and activity of proteins in membranes but are difficult to detect and analyse. This review covers current approaches to studying membrane protein interactions. In addition to standard biochemical and genetic techniques, the classic yeast nuclear two-hybrid system has been highly successful in identification and characterization of soluble protein-protein interactions. However, classic yeast two-hybrid assays do not work for membrane proteins because such yeast-based interactions must occur in the nucleus. Here, we highlight recent advances in yeast systems for the detection and characterization of eukaryote membrane protein-protein interactions. We discuss these implications for drug screening and discovery.