The tumor suppressor p53 provides an important barrier to the initiation and maintenance of cancers. As a consequence, p53 function must be inactivated for a tumor to develop. This is achieved by mutation in approximately 50% of cases and probably by functional inactivation in the remaining cases. We have previously shown that the second messenger cAMP can inhibit DNA damage-induced wild-type p53 accumulation in acute lymphoblastic leukemia cells, leading to a profound reduction of their apoptotic response. In the present article, we provide a mechanistic insight into the regulation of p53 levels by cAMP. We show that increased levels of cAMP augment the binding of p53 to its negative regulator HDM2, overriding the DNA damage-induced dissociation of p53 from HDM2. This results in maintained levels of p53 ubiquitination and proteasomal degradation, which in turn counteracts the DNA damage-induced stabilization of the p53 protein. The apoptosis inhibitory effect of cAMP is further shown to depend on this effect on p53 levels. These findings potentially implicate deregulation of cAMP signaling as a candidate mechanism used by transformed cells to quench the p53 response while retaining wild-type p53.