Infertility is defined by the World Health Organization as the inability to conceive naturally after one year of regular unprotected intercourse. Both males and females are equally responsible for the causes. It has been estimated that approximately 7% of the male population is affected by infertility, mainly due to the alteration of spermatogenesis, a complex and tightly coordinated process taking place in the seminiferous tubules that leads to sperm production starting from puberty. The last decade has witnessed huge advances in the understanding of the molecular basis of several pathological conditions affecting sperm production and maturation, thus providing new interesting clues that impact most recent reproductive technologies. In this Special Issue, we want to provide a global overview of human male infertility ranging from the genetic causes to the molecular and endocrine aspects of disease pathogenesis. This Issue will also cover new advances in preclinical therapeutic strategies, including the in vitro recapitulation of the spermatogenesis process to the pharmacological management of infertile patients.