Studies from autopsy data and malpractice claims consistently identify diagnostic errors as a prominent cause of preventable morbidity and mortality, but as yet error prevention has focused on other areas of patient safety. This commentary discusses individual and systems factors that lead to diagnostic error and proposes steps toward minimizing such problems. In particular, the authors recommend focusing on misdiagnosis-related harm in specific clinical scenarios and using information technology to build decision support into routine clinician work flow. An AHRQ WebM&M perspective discussed cognitive biases that lead to diagnostic error.