Turner and Klinefelter syndromes are the most common chromosome abnormalities compatible with life. Prader-Willi syndrome is a complex multisystem imprinting disorder characterized by hypothalamic dysfunction, neurological implications, and psychiatric disturbances. All three conditions are associated with progressively increasing risk for metabolic and autoimmune morbidity and mortality. This chapter focuses on the endocrine aspects of these syndromes and recent discoveries based on epigenetics and gene expression studies that have broadened our understanding of their extensive phenotypic variability and heterogeneous comorbidities.