Oxytocin is a hypothalamic-posterior pituitary hormone with multiple effects, ranging from regulation of energy homeostasis to bone health and psychological wellbeing, in addition to its well-known effects in labor and lactation. Patients with hypothalamic and pituitary damage have a higher risk for medical and psychiatric comorbidities despite standard-of-care hormone replacement, and a clinically relevant oxytocin deficient state has been identified in patients with arginine vasopressin deficiency (formerly known as central diabetes insipidus) in the last decade. Therefore, oxytocin deficiency in patients with hypothalamic and pituitary damage is an emerging field. While intranasal oxytocin is readily available to patients, it is not FDA-approved in the US and the quality of compounded formulations is unclear. In addition, more research is needed to establish safety and efficacy of oxytocin-based therapeutics in patients with hypothalamic and pituitary damage before recommending treatment. This Review summarizes the current knowledge of the oxytocin system, oxytocin deficiency in other clinical conditions and relevance to patients with hypothalamic and pituitary damage. We highlight emerging data supporting oxytocin deficiency in hypothalamic-pituitary disease, diagnostic challenges, development of therapeutic strategies, and future research directions to advance the field.