Erectile dysfunction (ED) is a prevalent form of male sexual dysfunction. Phosphodiesterase type 5 (PDE5) inhibitor is the first-line treatment for ED. Numerous well-designed and -conducted clinical trials and postmarketing studies have established the safety and efficacy of PDE5 inhibitors for the treatment of ED. Ever since the first approval of sildenafil in 1998, PDE5 inhibitors have had several advances in their clinical use. More new agents with different pharmacokinetic profiles and new formulations were marketed. Conventional on-demand administration expanded to daily dosing. These advances provide more flexibility in clinical treatment of ED for patients and physicians. Moreover, clinical indications of PDE5 inhibitors extend from treatment of ED to pulmonary arterial hypertension and signs and symptoms of benign prostatic hyperplasia because of the distribution of PDE5 enzyme in human organs and tissues. The evolution of PDE5 inhibitors heralds a remarkable medical history from bench to clinical practice.