There is significant animal model data demonstrating a benefit of testosterone on both inflammatory and neuroprotective mechanisms relevant to multiple sclerosis (MS). Several studies have demonstrated lowered testosterone levels in up to 40% of men with MS. Lower testosterone levels were correlated with worsened scores of physical and cognitive disability. There is increasing data suggesting a role of testosterone in MS risk. A pilot study has demonstrated significant benefits of testosterone replacement therapy on cognitive, radiological, and immunological outcome measures in men with MS. Larger studies in other conditions have demonstrated concerns in terms of cardiovascular risk, which indicate the need for careful monitoring upon administration to MS patients. Further studies are needed to develop safer testosterone preparations, which preserve its multiple beneficial effects, as well as multicenter clinical trials to evaluate safety, dosing, and efficacy in larger populations of men with MS. Additionally, studies are needed to further explore the role of androgens as a risk factor for MS, particularly at key life transitions.