Hypogonadism is a frequent condition, in particular during adult age. Whereas no doubts exist on the opportunity of treating patients with hypogonadism deriving from definite conditions affecting the hypothalamic-pituitary-testicular axis, more concerns are present for the treatment of men with age-related testosterone (T) decline, the so-called late-onset hypogonadism (LOH). Several options are available for treating hypogonadism, and the choice should be made according to rationale, indications, and expected outcomes, taking also into account the advantages and disadvantages associated with each molecule and preparation. Although gonadotropin-releasing hormone (GnRH) and gonadotropins are the cornerstone of therapy in secondary hypogonadism (sHG) men requiring fertility, few data are present on their use in LOH. Testosterone replacement therapy (TRT) is the most studied therapy in this particular and controversial condition. Randomized clinical trials (RCTs) on TRT are few and short lasting. However, there is substantial consistency on the efficacy of TRT in improving sexual function, increasing lean mass, and decreasing fat mass. The results are more controversial on the effectiveness of TRT in improving glycolipid profile and mood. Concerning bone mineral density and fractures, the evidence is scarce. The intense debate pursued over the last decades on the putative risk of cardiovascular (CV) events associated with TRT has been blunted by the results of the TRAVERSE trial, which reassured on CV safety of TRT also in middle-aged and elderly men at high CV risk. However, continued caution is warranted to ensure that TRT is administered strictly within the framework of current guideline recommendations.