Dyspepsia is a complex disorder with several distinct pathophysiologic mechanisms that are still poorly understood. Patients who experience dyspepsia have a high burden of disease, with significant personal and economic costs. Although serious pathology presenting as dyspepsia is rare, clinicians need to be aware of alarm features that should trigger prompt referral for subspecialty care. Those without alarm features can be managed in a rational way with either empiric antisecretory therapy, test-and-treat for H pylori eradication, antidepressants, and psychotherapy, or a combination of these. Given the heterogeneity of symptoms and large variability in response to different treatments, more research into specific pathophysiologic mechanisms will likely help guide diagnosis and treatment choices in the future.