Background: Diagnosis errors are frequent and important, but represent an underemphasized and understudied area of patient safety. Diagnosis errors are challenging to detect and dissect. It is often difficult to agree whether an error has occurred, and even harder to determine with certainty its causes and consequence. The authors applied four safety paradigms: (1) diagnosis as part of a system, (2) less reliance on human memory, (3) need to open “breathing space” to reflect and discuss, (4) multidisciplinary perspectives and collaboration. Methods: The authors reviewed literature on diagnosis errors and developed a taxonomy delineating stages in the diagnostic process: (1) access and presentation, (2) history taking/collection, (3) the physical exam, (4) testing, (5) assessment, (6) referral, and (7) followup. The taxonomy identifies where in the diagnostic process the failures occur. The authors used this approach to analyze diagnosis errors collected over a 3-year period of weekly case conferences and by a survey of physicians. Results: The authors summarize challenges encountered from their review of diagnosis error cases, presenting lessons learned using four prototypical cases. A recurring issue is the sorting-out of relationships among errors in the diagnostic process, delay and misdiagnosis, and adverse patient outcomes. To help understand these relationships, the authors present a model that identifies four key challenges in assessing potential diagnosis error cases: (1) uncertainties about diagnosis and findings, (2) the relationship between diagnosis failure and adverse outcomes, (3) challenges in reconstructing clinician assessment of the patient and clinician actions, and (4) global assessment of improvement opportunities. Conclusions and recommendations: Finally the authors catalogue a series of ideas for change. These include: reengineering followup of abnormal test results; standardizing protocols for reading x-rays/lab tests, particularly in training programs and after hours; identifying “red flag” and “don't miss” diagnoses and situations and use of manual and automated check-lists; engaging patients on multiple levels to become “coproducers” of safer medical diagnosis practices; and weaving “safety nets” to mitigate harm from uncertainties and errors in diagnosis. These change ideas need to be tested and implemented for more timely and error-free diagnoses.