SummaryThe Ccr4–Not complex is a global regulator of transcription that affects genes positively and negatively and is thought to modulate the activity of TFIID. In the present work, we provide evidence that the Ccr4–Not complex may contribute to transcriptional regulation by the Ras/cAMP pathway. Several observations support this model. First, Msn2/4p‐dependent transcription, which is known to be under negative control of cAMP‐dependent protein kinase (PKA), is derepressed in all ccr4–not mutants. This phenotype is paralleled by specific post‐translational modification defects of Msn2p in ccr4–not mutants relative to wild‐type cells. Secondly, mutations in various NOT genes result in a synthetic temperature‐sensitive growth defect when combined with mutations that compromise cells for PKA activity and at least partially suppress the effects of both a dominant‐active RAS2Val‐19 allele and loss of Rim15p. Thirdly, Not3p and Not5p, which are modified and subsequently degraded by stress signals that also lead to increased Msn2/4p‐dependent activity, show a specific two‐hybrid interaction with Tpk2p. Together, our results suggest that the Ccr4–Not complex may function as an effector of the Ras/cAMP pathway that contributes to repress basal, stress‐ and starvation‐induced transcription by Msn2/4p.