<p>The hypothalamus orchestrates energy homeostasis via specialized neuronal populations and glial cells that integrate interoceptive signals, such as leptin, glucose, and fatty acids, through key intracellular energy sensors, like AMP-activated protein kinase (AMPK). This enables the hypothalamus to coordinate behavioral, autonomic, and neuroendocrine responses that regulate adipose mass and metabolism. This foundational Neuroendocrinology paradigm, forged through centuries of research, drives the mission of this Special Issue. From the cellular complexity of hypothalamic circuits and their hormonal regulation, to sex dimorphism and clinical relevance, as well as cutting-edge advances, such as single-cell hypothalamic mapping, circuit dynamics, and emerging therapeutic frontiers, this collection offers a comprehensive roadmap to the past, present and especially the future of hypothalamic regulation of energy homeostasis.</p>