There is a rising concern about developing innovative, efficacious PDE5I molecules that provide better safety, efficacy, and tolerability with less adverse effects. Innovative PDE5I with dual targets have also been defined in the literature. Additionally, some of PDE5I are able to selectively inhibit other enzymes such as histone deacetylase, acetylcholine esterase, and cyclooxygenase or act as nitric oxide donors. This review presents knowledge concerning the advanced trends and perspectives in using PDE5I in treatment of ED and other conditions.