Uncertainty is inherent to the medical profession. Medical profession incorporates science and the scientific method with the art of being a physician. Every decision a clinician makes has some degree of uncertainty in it. There are several factors which result in medical uncertainty during clinical practice, and this could arise from physicians as well as patient factors, from test and treatment characteristics and practice environment. The inability to come at a conclusion, despite a thorough and reasonable evaluation generates anxiety amongst patients and physicians and the relationship between them may become strained and unproductive. Personal tolerance to ambiguity and uncertainty also plays a significant role in medical students when it comes to career choice. Medical Uncertainty may be technical, personal or conceptual. In the era of information overload and ‘evidence based medicine’ where guidelines, protocols and algorithms are available for every symptom complex and disease, one would expect medical uncertainty to be less if not totally eliminated but that is actually not the case. In fact, the protocols also threaten to depersonalize the relationship between the doctor and the patient. This article reviews the underlying mechanisms, causes and effects of medical uncertainty and also some methods to reduce uncertainty in today’s clinical practice.