Diagnostic errors contribute to as many as 70% of medical errors. Prevention of diagnostic errors is more complex than building safety checks into health care systems; it requires an understanding of critical thinking, of clinical reasoning, and of the cognitive processes through which diagnoses are made. When a diagnostic error is recognized, it is imperative to identify where and how the mistake in clinical reasoning occurred. Cognitive biases may contribute to errors in clinical reasoning. By understanding how physicians make clinical decisions, and examining how errors due to cognitive biases occur, cognitive bias awareness training and debiasing strategies may be developed to decrease diagnostic errors and patient harm. Studies of the impact of teaching critical thinking skills have mixed results but are limited by methodological problems.This Perspective explores the role of clinical reasoning and cognitive bias in diagnostic error, as well as the effect of instruction in metacognitive skills on improvement of diagnostic accuracy for both learners and practitioners. Recent literature questioning whether teaching critical thinking skills increases diagnostic accuracy is critically examined, as are studies suggesting that metacognitive practices result in better patient care and outcomes. Instruction in metacognition, reflective practice, and cognitive bias awareness may help learners move toward adaptive expertise and help clinicians improve diagnostic accuracy. The authors argue that explicit instruction in metacognition in medical education, including awareness of cognitive biases, has the potential to reduce diagnostic errors and thus improve patient safety.