The cAMP response element-binding protein (CREB) is a stimulus-induced transcription factor that responds rapidly to phosphorylation and/or coactivator activation. Regulated activation of CREB has a significant impact on cellular growth, proliferation and survival. To overturn the cellular control of these processes, tumor cells have developed various mechanisms to achieve constitutive activation of CREB, including gene amplification, chromosome translocation, interaction with viral oncoproteins, and inactivation of tumor suppressor genes. These mechanisms converge on the phosphorylation of CREB and/or the activation of transducer of regulated CREB activity (TORC) coactivators to effect uncontrolled proliferation of cells. This minireview summarizes the different lines of existing evidence that support a direct role of CREB in oncogenesis.