Since the chemical identification, isolation, and synthesis of testosterone in the laboratory in 1930s, clinical as well as basic research studies ensued to evaluate the role of this endocrine hormone in human physiology and its impact on human health. The availability of testosterone formulations, such as testosterone esters made it possible to investigate the effects of testosterone treatments in various clinical conditions. Many studies reported on the benefits of testosterone therapy, with no apparent harm were reported between 1938 and 1950. However, the report by Huggins in 1941 suggesting that testosterone treatment of men with metastatic prostate cancer caused re-growth of this disease raised serious concerns regarding the safety of testosterone therapy and created an enormous fear among clinicians and patients. It took several decades of intense clinical research to demonstrate that testosterone is not a carcinogen and does not promote prostate cancer. Another uncertainty emerged due to reports of increased risk of cardiovascular disease, contributing to fear that testosterone therapy is harmful. The findings of a large, randomized placebo-controlled, study (TRAVERSE Trial) provided unequivocal evidence of benefits and safety of testosterone therapy. In this trial, no increased risk of prostate cancer or cardiovascular disease were reported. In this chapter, we provide a concise summary of the history of testosterone therapy in men with testosterone deficiency and discuss the challenges encountered along this endeavor, highlighting the plethora of evidence presented by more than 120 clinical research studies documenting the benefits and safety of testosterone therapy in men with testosterone deficiency.