Speculation regarding dysregulation of cAMP metabolism in oncogenesis has existed since the discovery of cAMP more than 50 years ago. Recent data confirm the relevance of disordered cAMP metabolism to the genesis of multiple cancers and suggest that the mechanism might involve altered expression and activity of phosphodiesterases (PDEs). These discoveries coincide with the rapid development and clinical evaluation of PDE inhibitors for non-cancer indications. Thus, the time is ripe to evaluate PDE inhibitors as cancer chemotherapeutics. Here we highlight recent evidence that abnormal regulation of cAMP levels might be a determinant of brain tumorigenesis and that altered PDE expression is one the mechanisms of its dysregulation. Recent preclinical and clinical experience with inhibitors of PDE4 indicates that this might be a promising approach to brain tumor therapy.