Erectile dysfunction (ED) is a major health problem as the population ages. Basic science research for the last two decades has expanded the knowledge on ED and identified several key molecular changes associated with the pathogenesis of ED, including nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) / protein kinase G (PKG) pathway, RhoA/Rho-associated protein kinase (ROCK) signaling pathway, reactive oxygen species (ROS), renin-angiotensin system (RAS) and tumor necrosis factor-alpha (TNF-α). The causes of ED are classified into aging, vasculogenic, neurogenic, endocrinological, drug-induced and psychogenic. ED is often associated with systemic diseases, such as diabetes and cardiovascular diseases. In this review, we will review the molecular mechanisms of ED and known mechanisms behind ED associated with systemic diseases.