Differential diagnosis is the systematic process of distinguishing between conditions that share similar clinical features. The clinician must develop and refine a problem representation, generate a differential list, and strategically order tests to rule in or rule out competing diagnoses. The diagnostic reasoning process follows a structured approach: (1) gather clinical data through history and physical examination, (2) create a problem representation summarizing the key features (age, sex, acuity, key symptoms, pertinent positives and negatives), (3) generate a differential diagnosis list using pattern recognition and analytic reasoning, (4) prioritize differentials by probability and severity (must-not-miss diagnoses), and (5) order targeted diagnostics to confirm or exclude leading diagnoses. Cognitive biases significantly affect diagnostic accuracy. Anchoring bias occurs when the clinician fixates on an initial impression. Premature closure stops the diagnostic process too early. Availability bias overestimates diagnoses recently encountered. Confirmation bias selectively seeks information supporting the initial hypothesis. The clinician must employ deliberate diagnostic reasoning strategies and metacognition to mitigate these biases. Chest pain differential diagnosis illustrates the systematic approach. The must-not-miss diagnoses include acute coronary syndrome (MI, unstable angina), aortic...