The regulatory subunit of cAMP‐dependent protein kinase (PKA) exists in the isoforms RI and RII, which distinguish PKA isozymes type I (PKA‐I) and type II (PKA‐II). Evidence obtained from different experimental approaches—such as site‐selective cAMP analogs, antisense oligonucleotides, transcription factor decoys, cDNA microarrays, and gene transfer—has shown that PKA‐I and ‐II are expressed in a balance of cell growth and differentiation. Loss of this balance may underlie cancer genesis and progression. DNA microarrays demonstrate that antisense suppression of the RIα, which upregulates RIIβ, downregulates a wide range of genes involved in cell proliferation and transformation while upregulating cell differentiation and reverse transformation genes in PC3M prostate tumors that undergo regression. Conversely, the vector‐mediated overexpression of RIIβ, as opposed to those of RIα and Cα, exhibits induction of differentiation genes along with suppression of cell proliferation and transformation genes leading to reversion of tumor phenotype. Thus, switching of PKA isozyme can cause tumor cells to undergo phenotypic reversion of the malignancy.