The yeast two-hybrid system is a genetic method that detects protein-protein interactions. One application is the detection by library screening of new interactors of a protein of known function. In the August issue of Nature Genetics, Fromont-Racine et al. 1 showed for the first time that the construction of the protein interaction map of a complex pathway, such as that of the mRNA splicing machinery, is now possible, because of the combination of recent technical improvements elaborated in several laboratories. With a yeast cell mating procedure that increases screen efficiency, they used their complex yeast genomic library of 5 ϫ 10 6 clones to test 700 ϫ 10 6 interactions against 15 proteins. They identified and classified 170 potential interactors, including approximately 70 proteins of previously unknown function. More than 25% of the interactors are probably biologically relevant. The achievements of Fromont-Racine et al. have opened the way to the systematic analysis of the protein interaction networks of the 6,000 open reading frames-yeast proteome. This task requires, however, automation of the library screens and creation of a two-hybrid library database.