Introduction: The role of testosterone (T) replacement therapy (TRT) in men is still conflicting. In particular, safety concerns and cardiovascular (CV) risk related to TRT have not been completely clarified yet. Similarly, the clear beneficial effects of TRT are far to be established. Aim: To systematically and critically analyze the available literature providing evidence of the benefit-risk ratio derived from TRT in aging men. Methods: A comprehensive PubMed literature search was performed to collect all trials, either randomized controlled trials (RCTs) or observational studies, evaluating the effects of TRT on different outcomes. Main Outcome Measure: Whenever possible, data derived from RCTs were compared with those resulting from observational studies. In addition, a discussion of the available meta-analyses has been also provided. Results: Data derived from RCT and observational studies clearly documented that TRT can improve erectile function and libido as well as other sexual activities in men with hypogonadism (total T < 12 nM). Conversely, the effect of TRT on other outcomes, including metabolic, mood, cognition, mobility, and bone, is more conflicting. When hypogonadism is correctly diagnosed and managed, no CV venous thromboembolism or prostate risk is observed. Clinical Implications: Before prescribing TRT, hypogonadism (total T < 12 nM) must be confirmed through an adequate biochemical evaluation. Potential contraindications should be ruled out, and an adequate follow-up after the prescription is mandatory. Strength & Limitations: When correctly diagnosed and administered, TRT is safe, and it can improve several aspects of sexual function. However, its role in complicated vasculogenic erectile dysfunction is limited. Conversely, TRT is not recommended for weight reduction and metabolic improvement. Further well-powered studies are advisable to better clarify TRT for long-term CV risk and prostate safety in complicated patients as well as in those curatively treated for prostate cancer. Conclusion: TRT results in sexual function improvement when men with hypogonadism (total T < 12 nM) are considered. Positive data in other outcomes need to be confirmed.