Sound diagnostic reasoning is a defining characteristic of the expert clinician. The prevailing psychological model of reasoning describes two systems of thought: a fast, intuitive, but biased (System 1) and a rigorous, analytic, but slow (System 2). Clinicians use both systems during diagnostic reasoning but tend to lean toward a System 1-dominant approach as they get more experienced. This represents a potential source of diagnostic error, perhaps amenable to deliberate System 2 thinking. In this review, first principles reasoning is suggested as a method of System 2 thinking in a diagnostic context. .