Although our knowledge about the function of basic biological elements such as genes and proteins has grown considerably, we lack a comprehensive picture of how these elements act in coordination, and our ability to modulate their function is still limited. Here, I propose a global study of motif-mediated protein interactions that aims to find interactions that can be modulated by small molecules or peptides, and their roles in the organization of signaling pathways. I will use one of the best-understood eukaryotic model organism Saccharomyces cerevisiae, for which several large-scale functional, interaction and chemical-genetic datasets are available. In addition, the genome sequences for more than a dozen of yeast species are largely complete. I will identify motif-mediated interactions using these proteomic and comparative data, and integrate them with large-scale chemical-genetic datasets to explore the correlations between genetic interactions and small molecules. I will test my predictions and study cellular pathways cross-talk using modelling and combinatorial protein interaction interference. With such a systematic approach, I aim to reveal the fundamental principles of how protein function can be modulated, and how these principles might carry over to vertebrates.