Selective phosphodiesterase type-5 (PDE5) inhibitors such as sildenafil, vardenafil and tadalafil are commonly used first-line therapy for erectile dysfunction (ED). The safety and high tolerability of these drugs has garnered substantial interest among researchers to investigate further beneficial nonerectogenic uses for such drugs. PDE5 expression has shown to be increased in several human malignancies, suggesting that this enzyme may play a role in tumorigenesis. This is supported by the reported anticancer activity of PDE5 inhibitors such as exisulind and its analogs, as well as vardenafil. Further, PDE5 inhibitors have recently been reported to sensitize certain types of cancer to standard chemotherapeutic drugs. The aim of this review is to shed some light on the existing preclinical evidence supporting the use of PDE5 inhibitors as potential effective adjuncts in cancer chemotherapy and even as anticancer agents. I also showed our recent unpublished data with regard to the promising antitumor activity of vardenafil, a potent PDE5 inhibitor, against brain cancer.