Significant unintentional weight loss in a previously healthy individual is often a harbinger of underlying systemic disease. The routine medical history should always include inquiry about changes in weight. Rapid fluctuations of weight over days suggest loss or gain of fluid, whereas long-term changes usually involve loss of tissue mass. Loss of 5% of body weight over 6–12 months should prompt further evaluation. Gradual weight loss is physiologic in persons aged >80, but this demographic group also has a high risk for malignancy or other serious illness.