¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Beyazit, 34116, Istanbul, Türkiye DOI : 10.29228/jrp.512 Phosphodiesterases (PDEs) consist of an enzyme family of eleven groups responsible for the hydrolytic breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). cAMP and cGMP are important secondary messengers that regulate physiological functions. The widespread expression of PDE3 in tissues and organs makes it an attractive therapeutic target. For decades, PDE3 inhibitors have been acknowledged as significant pharmaceutical agents in the treatment of cardiovascular disorders due to their inotropic and vasodilatory actions. Emerging data, however, suggests that the potential therapeutic application of PDE3 inhibitors has gone beyond their traditional cardiovascular applications. This comprehensive review aims to explore the noncardiovascular developments related to PDE3 inhibitors, exploring their mechanism of action, and clinical trials. Keywords : phosphodiesterase; PDE3 inhibitors; drug repositioning; respiratory disease; anti-inflammatory disease; anticancer; COVID-19