Unintentional weight loss (UWL) is a common symptom, particularly among older patients. In one site, patients with UWL have increased morbidity and mortality; in the other site, the prognosis of the patients is related to primary cause of the UWL. The differential diagnosis of the underlying diseases leading to UWL is broad and includes both malignant and nonmalignant gastrointestinal (GI) diseases, as well as endocrine, infectious, cardiopulmonary, and psychiatric disorders and side effects of medications. Patients with UWL should be investigated. The diagnostic approach to patients with UWL includes comprehensive medical history, physical examination, laboratory testing, imaging, and endoscopy. The imaging and endoscopy should be targeted according to the symptom, physical examination findings, and laboratory results. The treatment of UWL should be targeted to the primary disease causing weight loss. Non-pharmacologic nutrition intervention is the important treatment, and some pharmacologic treatment could be helpful in part of the patients.