Azoospermia, the complete absence of sperm in the ejaculate, affects up to 1% of the male population and poses a significant challenge in reproductive medicine. While assisted reproductive technologies (ART) remain central to achieving parenthood in azoospermic men, there is a growing recognition of the role of targeted medical treatment in improving reproductive outcomes. This chapter reviews the physiological basis of spermatogenesis and explores the rationale, evidence, and clinical strategies for hormonal therapy in azoospermia, with a particular focus on hypogonadotropic hypogonadism and idiopathic nonobstructive azoospermia (NOA). Emphasis is placed on the APHRODITE classification system, a novel framework that stratifies men based on endocrine and seminal parameters to guide therapeutic decision-making. Gonadotropin-based regimens, selective estrogen receptor modulators, and aromatase inhibitors are discussed in the context of restoring spermatogenesis or improving the success of surgical sperm retrieval. Real-world data, including recent studies on hormonal priming before microdissection testicular sperm extraction (micro-TESE), are critically appraised. The chapter underscores the clinical and research implications of a personalized, physiology-driven approach to azoospermia, offering renewed hope for selected patients historically considered untreatable.