Introduction: Treatment options for erectile dysfunction (ED) have evolved over the last two decades, particularly after the introduction of phosphodiesterase type-5 inhibitors (PDE5Is). The path, however, has not been straightforward with issues raised regarding safety and toxicity following ED treatments. Areas covered: A literature review was conducted on current evidence related to the safety of PDE5Is, intracavernosal injections and various older forms of oral therapies. Relevant trials were identified through a literature search of PubMed from 1980 to 2019. Expert opinion: PDE5Is are now recommended as the first line therapy for the treatment of ED due to their efficacy and tolerable side effects. Comparison of the various PDE5Is on safety has not been supported by prime evidence, and consequently, the negative aspects of each inhibitor appear the same as defined in the literature. Other means of therapies for ED are still in the running, and these also present a different range of side effects. While intracavernosal injections have potential to cause priapism and penile fibrosis, intraurethral alprostadil may result in more systematic side effects. Alternative topical ED therapies are generally limited with their local side effects.