Medicine is a science of uncertainty and an art of probability.-William Osler 1 Reduction of uncertainty is essential to the practice of medicine, but elimination of uncertainty is impossible.-Benjamin Djulbegovic and Sander Greenland 2 Uncertainty is inherent in the practice of medicine. Dermatologists can never be completely certain that a benign-appearing skin lesion is not a skin cancer; radiologists cannot be certain that changes on a chest radiograph are the result of pneumonia. No diagnostic test is 100% accurate, and even with additional testing such as a biopsy or a computed tomography (CT) scan, some degree of uncertainty remains. Until recently, physicians have had little choice but to tolerate uncertainty. Clinical radiography and electrocardiography did not become available until the end of the 19th century, and many other diagnostic tests have become part of routine clinical practice only in the past few decades. Uncertainty has always been a reality, but increased availability of diagnostic options means that the physician's response to uncertainty is now an important factor in clinical care.