This special issue is fully dedicated to the topic of azoospermia and contains the seminal work of renowned scientists and clinicians from seven countries on three continents. In seventeen chapters, a comprehensive review of the epidemiology, genetics, physiopathology, diagnosis, and management of azoospermia addresses our current knowledge on the topic. The clinical results of assisted reproductive techniques applied to this category of male infertility and the health of offspring originating from such fathers are critically analyzed. In addition, the challenges and the future biotechnological perspectives for the treatment of azoospermic males seeking fertility are discussed.