This narrative review synthesizes current evidence on the medical management of nocturnal polyuria, including antidiuretic replacement therapy as well as other emerging modalities, with particular emphasis on areas of active investigation and future research directions. Relative to earlier formulations, the pharmacological profiles of novel desmopressin acetate nasal spray and orally disintegrating tablet formulations appear favorable in optimizing the balance between efficacy and safety. Additionally, several highly selective small-molecule arginine vasopressin 2 receptor agonists are under active development, while appropriately timed short-acting diuretics, pharmacotherapy for hypertension, nonsteroidal anti-inflammatory drugs, and sex hormone replacement therapy are also a focal point of extensive ongoing nocturnal polyuria research. Emerging laboratory technologies now make feasible a sub-stratification of nocturnal polyuria patients into substrate-based phenotypes for individualized treatment. An increasingly refined understanding of the pathogenesis of nocturnal polyuria, and arginine vasopressin dysregulation in particular, has also introduced new opportunities for point-of-care testing in patients with nocturnal polyuria.