The emergence of cisplatin resistance poses a major problem to the successful treatment of a variety of human malignancies. Therefore, understanding the molecular mechanisms that underlie cisplatin resistance could significantly improve the clinical efficacy of this cytotoxic agent. Various studies have described that cellular sensitivity to cisplatin can be influenced by several signal transduction pathways. In this review, we examine the role of the cyclic AMP-dependent protein kinase (PKA) in the modulation of drug resistance in cancer. By a somatic mutant genetic approach, the role of PKA in the development of resistance to chemotherapeutic agents has been investigated. A series of mutants with decreased PKA activity was examined for their sensitivity to cisplatin. PKA mutants with defective regulatory (RIalpha) subunits, but not altered catalytic (C) subunits, exhibit increased resistance to cisplatin, as well as other DNA-damaging agents. Furthermore, since RIalpha subunit mutants show enhanced DNA repair we, therefore, hypothesize that functional inactivation of PKA may result in increased recognition and repair of cisplatin lesions. Alternatively, it seems likely that mutation of the RIalpha subunit may affect cellular sensitivity to various anticancer drugs, suggesting that the RIalpha subunit may have other physiological functions in addition to inhibiting the kinase activity of the C subunit. Therefore, exploitation of cyclic AMP levels or functional alteration of the R subunit may potentiate the cytotoxicity of chemotherapeutic agents and circumvent drug resistance in cancer. More importantly, the altered pattern and mechanism of drug resistance may offer the opportunity to investigate novel regulatory functions of the RIalpha subunit of PKA.