Despite major breakthroughs in the last few years, fundamental questions remain concerning the pathophysiology of leptin action in the brain. How does leptin access its brain targets? Is there any post-receptor defect in the brain of obese individuals? A better understanding of leptin’s neuroendocrine function is also needed. Particularly, how does leptin modulate the release of hypothalamic neuropeptides and pituitary hormones? Progress in these fronts will help to elucidate the role of leptin in the therapy of different hypothalamic/pituitary pathologies, such as delayed puberty, growth defects, or bone metabolism abnormalities.