Yohimbine, a pharmacologically well-characterized alpha-2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. In-depth, systematic studies in animals have shown that the drug has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigorous human clinical trials. Although relevant basic pharmacological and animal research information has been available for over 15 y, recent studies were designed with a lack of insight and complete disregard of those fundamental studies. Currently, dose-response investigations are not available, alternative routes of administration (i.e. sublingual) have not been investigated, nor has continuous versus 'on-demand' administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessment of various populations was carried out in very limited cohorts and only in most general terms. In short, properly designed trials in humans have not been done. Why? Yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about (as recently happened with two other agents: phentolamine and apomorphine), serious investigations of yohimbine will remain in limbo. It could be that the nay sayers are right and yohimbine, indeed, lacks clinical activity as a treatment for men with erectile dysfunction. As long as it remains an orphan drug, we will never know.