The cAMP dependent protein kinase (A-kinase) is one of the first and best studied kinases in mammalian cells. There is extensive evidence that A-kinase activity acts antagonistically toward mitotic entry both in oocyte and somatic cells. Firstly, A-kinase seems to directly compromise the activation process of the cdc2 cyclin B mitotic kinase. Secondly, as shown by specific in vivo inhibition of A-kinase using microinjection of a stable form of its inhibitor peptide PKI, A-kinase modulates several key interphase cellular processes including cytoskeletal dynamics, transcription, chromatin structure and nuclear localization. We discuss the potential mechanisms involved in the down regulation of A-kinase activity at the interphase/mitosis transition.