The mitogen-activated protein kinase (MAPK) signaling network is integrated into most, if not all, defined homeostatic and regulatory responses of eukaryotic cells. A systematic experimental and computational approach has been used to identify more than 2,000 protein interactions related to functions and regulation of the MAPK signaling network. This discovery process provides a rich data and reagent resource for defining complexities of protein networks involving MAPKs and control of cellular physiology.