Decisions of when to order and how to interpret diagnostic tests form the cornerstone of medical care. However, interpreting a patient's test results in the context of their clinical presentation is not always straightforward. The objective rigor of diagnostic tests may be perceived as providing superior information, compared to the clinical evaluation. Prior studies demonstrate that clinicians at all levels of experience and fields of expertise may not consistently incorporate two critical points of uncertainty in diagnostic decision making: imperfect test accuracy and the pre-test probability of the disease being investigated. This book highlights some pitfalls in diagnostic reasoning in this regard, and emphasizes strategies to incorporate clinical and diagnostic information, including uncertainty therein, to optimize diagnostic reasoning.