Many diseases have multifactorial origins. There is increasing evidence that mild dehydration plays a role in the development of various morbidities. In this review, effects of hydration status on acute and chronic diseases are depicted (excluding the acute effects of mild dehydration on exercise performance, wellness, cognitive function, and mental performance) and categorized according to four categories of evidence (I-IV). Avoidance of a high fluid intake as a precautionary measure may be indicated in patients with cardiovascular disorders, pronounced chronic renal failure (III), hypoalbuminemia, endocrinopathies, or in tumor patients with cisplatin therapy (IIb) and menace of water intoxication. Acute systemic mild hypohydration or dehydration may be a pathogenic factor in oligohydramnios (IIa), prolonged labor (IIa), cystic fibrosis (III), hypertonic dehydration (III), and renal toxicity of xenobiotica (Ib). Maintaining good hydration status has been shown to positively affect urolithiasis (Ib) and may be beneficial in treating urinary tract infection (IIb), constipation (III), hypertension (III), venous thromboembolism (III), fatal coronary heart disease (III), stroke (III), dental disease (IV), hyperosmolar hyperglycemic diabetic ketoacidosis (IIb), gallstone disease (III), mitral valve prolapse (IIb), and glaucoma (III). Local mild hypohydration or dehydration may play a critical role in the pathogenesis of several broncho-pulmonary disorders like exercise asthma (IIb) or cystic fibrosis (Ib). In bladder and colon cancers, the evidence on hydration status' effects is inconsistent.