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The actions of many extracellular stimuli are elicited by complexes of cell surface receptors, heterotrimeric guanine nucleotide–binding proteins (G proteins), and mitogen-activated protein kinase (MAPK) complexes. Analysis of haploid yeast cells and their response to peptide mating pheromones has produced important advances in the understanding of G protein and MAPK signaling mechanisms. Many of the components, their interrelationships, and their regulators were first identified in yeast. Examples include definitive demonstration of a positive signaling role for G protein βγ subunits, the discovery of a three-tiered structure of the MAPK module, development of the concept of a kinase-scaffold protein, and the discovery of the first regulator of G protein signaling protein. New and powerful genomic, proteomic, and computational approaches available in yeast are beginning to uncover new pathway components and interactions and have revealed their presence in unexpected locations within the cell. This updated Connections Map in the Database of Cell Signaling includes several major revisions to this prototypical signal response pathway.