Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH.