Over the past two decades several large cohort studies have been performed to disclose the changes of sex hormone in elderly and their clinical significance. Beyond the decline of total testosterone, aging is accompanied by a sex hormone binding globulin (SHBG) increase, a steeper free testosterone decline, while gonadotropins may be increased or inappropriately normal, with important contribution of comorbidities (e.g., obesity) to these changes. Actually, it has become firm the concept that the biochemical finding of testosterone deficiency alone is not sufficient for diagnosing hypogonadism in older men. The definition of late-onset hypogonadism (LOH) includes low serum testosterone levels coupled with signs and symptoms related to hypogonadism. Indeed, the combination of multiple factors all contributing to the testosterone decline, with other concurrent comorbidities further overlapping, makes the clinical correlates of LOH highly heterogeneous. For all these reasons both the diagnosis and the therapeutic management of LOH, especially the decision about starting testosterone replacement treatment, remain challenging.