The purpose of this research project was to elucidate novel regulatory mechanisms of the Pmk1 MAPK signaling pathway in fission yeast and its application to genome-based drug discovery. We performed chemicalgenomics screens, utilizing the functional interaction between MAPK and calcineurin, and identified regulators (such as Cwg2, Rho4 and Rho5) and targets of Pmk1 MAPK in addition to several compounds that modify the ERK MAPK signaling pathway in mammals. Furthermore, we performed genome-wide identification of the genes involved in the sensitivities to FK506, Rapamycin and FTY720 and elucidated as-yet-unidentified functional interactions between MAPK and these gene products. Collectively, our data will contribute to the development of novel and effective therapeutic approaches for diseases associated with abrogated MAPK signaling activity.