The past few years have been witness to a sea of change in understanding the diagnosis and treatment of erectile dysfunction. In the wake of Viagra, effective orally administered therapies are now the expected gold standard. Currently available therapies include both peripherally (at the level of the penis) and centrally (brain, e.g., hypothalamic nuclei) acting compounds. When all modes of pharmacotherapy are considered, ranging from oral, to topical, to intraurethral, to intracavernous injection, it is clear that the vast majority of men with mild to moderate erectile dysfunction can now be effectively treated. However, all forms of pharmacotherapy have the lowest efficacy and greatest side effect profiles (including cardiovascular events) in the patients that need the therapy most, that is, those with relatively severe and longstanding erectile dysfunction. The newer generation of pharmacotherapies, which will likely include gene therapy techniques as well, will therefore have to target this latter group. Improved mechanism-based, perhaps patient-specific therapies are foreseen that will dramatically increase the number of patients seeking treatment, as well as the quality of their lives.