Spermatogenic failure has been recognized as the most severe presentation of male infertility in humans. Although it usually results in azoospermia. Approximately 30 to 60% of such men have sparse foci of sperm production within their dysfunctional testes, which can be extracted and used for in vitro fertilization techniques to produce a viable offspring. The scope of spermatogenic failure-related infertility covers a wide spectrum from genetic studies to hormonal control, microsurgical and medical therapy to assisted reproduction techniques, as well as innovative stem cell research aiming at creating artificial gametes. From a medical perspective, the management of men with spermatogenic failure seeking fertility involves a series of steps that includes the differential diagnosis of azoospermia, selection of the candidates for surgical sperm retrieval using molecular biology diagnosis, identification of those who could benefit from medical and surgical interventions prior to sperm retrieval, application of the best method to surgically retrieve testicular spermatozoa, and the use of state-of-art in vitro fertilization techniques. A coordinated multidisciplinary effort involving urologists, andrologists, geneticists, reproductive endocrinologists and embryologists will offer the best possible chance of achieving a biological offspring to men with spermatogenic failure.