Salivary gland tumors, a group of histologically diverse benign and malignant neoplasms, represent a challenging problem for diagnosis and treatment. A specific recurring t(11;19)(q21;p13) translocation is associated with two types of salivary gland tumors, mucoepidermoid carcinomas and Warthin's tumors. This translocation generates a fusion protein comprised of the N‐terminal CREB (cAMP response element‐binding protein)‐binding domain of the CREB regulator MECT1 (Mucoepidermoid carcinoma translocated‐1) and the C‐terminal transcriptional activation domain of the Notch coactivator Mastermind‐like 2 (MAML2). Here, we demonstrate that the MECT1‐MAML2 fusion protein induces expression of multiple genes known to be CREB transcriptional targets. MECT1‐MAML2 was found to bind to CREB, recruit p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activate CREB‐dependent transcription. The transforming activity of MECT1‐MAML2 was markedly reduced by blocking CREB DNA binding. Thus, this fusion oncogene mimics constitutive activation of cAMP signaling, by activating CREB directly. This study has identified a novel, critical mechanism of transformation for an oncogene associated very specifically with salivary gland tumors, and identified potential targets for the development of novel therapies.