This manuscript overviews a series of pathophysiological mechanisms involved in the pathogenesis of obesity-related hypertension—such as leptin resistance, impaired baroreceptor and chemoreceptor reflexes, increased renal sympathetic nervous activity, mitochondrial dysfunction, the regulatory role of intermedin, adrenomedullin and sPRR—that could be the target of specific and selective therapeutic interventions in the innovative context of precision medicine. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.