Involuntary weight loss is a common finding and one associated with increased morbidity and mortality, especially in the elderly patient. The precise mechanisms by which weight loss occurs are currently being elucidated and probably involve the actions of classic hormones as well as cytokines, such as TNF (cachectin), adipsin, and interleukin-1 and interleukin-6. The differential diagnosis of involuntary weight loss is extensive, but case studies indicate that cancer, depression, and disorders of the gastrointestinal tract may be the most common causes. In approximately 25% of cases, no cause of weight loss is found despite extensive evaluation and prolonged follow-up. In the majority of cases, history, physical examination, and limited laboratory and radiologic studies reveal the cause of weight loss, when a cause is to be found. If an initial evaluation does not identify a cause, careful follow-up rather than undirected diagnostic testing is recommended. In the treatment of patients with involuntary weight loss, the underlying medical or psychiatric cause of the weight loss should be treated first if possible. Several medications are currently being investigated for treatment of patients with weight loss.