Abstract: The Ccr4-Not complex is a multifunctional regulatory platform composed of 9 subunits that controls diverse cellular events including mRNA degradation, protein ubiquitination, and transcription. In this study, we identified the yeast Saccharomyces cerevisiae osmotic and oxidative stress transcription factor Skn7, as a new target for regulation by the Ccr4-Not complex. Skn7 interacts with Not1 in a two-hybrid assay and co-immunoprecipitates with Not5 in a Not4-dependent manner. Skn7-dependent expression of OCH1 and Skn7 binding to the OCH1 promoter are increased in not4Delta or not5Delta mutants. Skn7 purified from wild-type cells but not from not4Delta cells is associated with the Srb10 kinase. This kinase plays a central role in the regulation of Skn7 by Not4, since increased OCH1 expression in not4Delta cells requires Srb10. These results reveal a critical role for the Ccr4-Not complex in the mechanism of activation of Skn7 that is dependent upon the Srb10 kinase.