Evaluation and treatment of males suspected of having testosterone deficiency entails multiple controversial issues. Recognition of the high prevalence of low testosterone levels in many men with common chronic diseases, an aging population, and greater recognition that testosterone levels fall with aging have greatly expanded the number of men who are diagnosed to have low testosterone levels. The development of new delivery systems and increased marketing of these delivery systems have combined with the larger number of potential patients to make testosterone replacement more common. It is a hot topic for the lay press and primary care clinicians, as well as for urologists and endocrinologists. Modern medicine is striving to provide evidence-based care. To do this we need large, randomized, placebo-controlled trials (RPCTs), preferably multicentered, and preferably government funded. Treatment of testosterone deficiency due to classical diseases affecting the hypothalamus, pituitary, and/or testes has been accepted for decades, although there were no multicenter trials. Some of the testosterone delivery systems predate the requirement for multicenter studies, and most of the more recently developed testosterone delivery systems were approved by the Food and Drug Administration on the basis of their pharmacokinetic profile and their ability to achieve physiological blood levels. Approval was not based on long-term studies of efficacy and risk. Some outcome studies have provided sufficient data to permit meta-analyses. However, most of these analyses have relied on a limited number of small clinical trials of short duration, and they have used a variety of testosterone delivery systems. Thus, their conclusions often are compromised. This review identifies many of the issues that continue to challenge clinicians, investigators, and patients. This is even truer for most busy primary care clinicians who write a large percentage of the prescriptions for testosterone treatment. Cunningham GR, Toma SM. Why Is Androgen Replacement in Males Controversial? J Clin Endocrinol Metab:jc.2010-0266. JCEM -- Sign In Page Context: Symptoms and signs consistent with androgen deficiency and low testosterone levels are recognized frequently in clinical practice. Recent population-based epidemiological studies indicate that low testosterone levels in men are associated with increased morbidity and mortality. The clinician must be able to counsel patients to help them determine whether testosterone replacement therapy is appropriate for them. Evidence Acquisition: The authors have conducted a literature search in PubMed, and we have reviewed references in the multiple systematic reviews and meta-analyses that have been published on this topic. Evidence Synthesis: We have attempted to provide the reader with an appreciation of the evidence that can be used to support the diagnosis of androgen deficiency, the efficacy of treatment, the potential risks of treatment, the therapeutic options, and the recommendations for monitoring treatment. Conclusions: We think that published clinical experience justifies testosterone replacement therapy in males who have not initiated puberty by age 14 and in males with low testosterone levels due to classical diseases of the hypothalamic-pituitary-gonadal axis. The benefit:risk ratio is less certain in older men and in those with chronic diseases associated with low testosterone levels. The decision to treat in this setting is much more controversial because there are few large clinical trials that have demonstrated efficacy and no large clinical trials that have determined potential risks of increasing the incidence of clinical prostate cancers or cardiovascular events. We provide a critical review of the evidence that supports treatment and potential risks and ways to reduce the risks if the physician and patient elect testosterone replacement.