Acute cholecystitis is the most common diagnosable cause for right upper quadrant abdominal (RUQ) pain in patients who present to the emergency department (ED). However, over one-third of patients initially thought to have acute cholecystitis actually have RUQ pain attributable to other causes. Ultrasonography (US) is the primary imaging modality of choice for initial imaging assessment and serves as a fast, cost-effective, and dynamic modality to provide a definitive diagnosis or a considerably narrowed list of differential possibilities. Multiple organ systems are included at standard RUQ US, and a variety of ultrasonographically diagnosable disease processes can be identified, including conditions of hepatic, pancreatic, adrenal, renal, gastrointestinal, vascular, and thoracic origin, all of which may result in RUQ pain. In certain cases, subsequent computed tomography, magnetic resonance (MR) imaging, MR cholangiopancreatography, or cholescintigraphy may be considered, depending on the clinical situation and US findings. Familiarity with the spectrum of disease processes outside of the gallbladder and biliary tree that may manifest with RUQ pain and recognition at US of these alternative conditions is pivotal for early diagnosis and appropriate management. Diagnosis at the time of initial US can reduce unnecessary imaging and its consequences, including excess cost, radiation exposure, nephrotoxic contrast medium use, and time to diagnosis, thereby translating into improved patient care and outcome. This article (a) reviews the causes of RUQ pain identifiable at US using an organ-system approach, (b) illustrates the US appearance of select conditions from each organ system with multimodality imaging correlates, and (c) discusses the relevant pathophysiology and treatment of these entities to aid in efficient direction of management. Online supplemental material is available for this article. ©RSNA, 2018.