Male hypogonadism is a clinical syndrome characterized by low testosterone and symptoms of androgen deficiency. Prostate cancer remains a significant health burden and cause of male mortality worldwide. The use of testosterone replacement therapy drugs is rising year-on-year for the treatment of androgen deficiency and has reached global proportions. As clinicians, we must be well versed and provide appropriate counseling for men prior to the commencement of testosterone replacement therapy. This review summarizes the current clinical and basic science evidence in relation to this commonly encountered clinical scenario. There is gathering evidence that suggests, from an oncological perspective, that it is safe to commence testosterone replacement therapy for men who have a combination of biochemically confirmed androgen deficiency and who have either had definitive treatment of their prostate cancer or no previous history of this disease. However, patients must be made aware and cautioned that there is a distinct lack of level 1 evidence. Calls for such studies have been made throughout the urological and andrological community to provide a definitive answer. For those with a diagnosis of prostate cancer that remains untreated, there is a sparsity of evidence and therefore clinicians are "pushing the limits" of safety when considering the commencement of testosterone replacement therapy.