Despite significant advances in scientific knowledge and technology, ambiguity and uncertainty are still intrinsic aspects of contemporary medicine. To practice confidently and competently, a physician must learn rational approaches to complex and ambiguous clinical scenarios and must possess a certain degree of tolerance of ambiguity. In this commentary, the authors discuss the role that ambiguity and uncertainty play in medicine and emphasize why openly addressing these topics in the formal medical education curriculum is critical. They discuss key points from original research by Wayne and colleagues and their implications for medical education. Finally, the authors offer recommendations for increasing medical student tolerance of ambiguity and uncertainty, including dedicating time to attend candidly to ambiguity and uncertainty as a formal part of every medical school curriculum.