Acquisition of diagnostic knowledge and improvement of patient health often are mutually exclusive goals. A perfect understanding of a disease process is only obtained through unrestricted testing that exposes the patient to adverse events and discomfort. In a patient completely undisturbed by test procedures, the physician remains ignorant about the nature of the disease. The interplay of diagnostic knowledge and patient health can be formulated in terms of an uncertainty principle, which allows one to mathematically derive the parameters that influence the balance between the two competing goals. The majority of clinical conditions permit the pursuit of perfect diagnostic knowledge. Occasional medical disasters occur because physicians underestimate the patient's functional reserve or the cumulative toll exerted by multiple tests. Especially in emergency situations or serious illness, the maximum amount of knowledge that can be achieved is far less than perfect. Under such circumstances, the best management option takes into account a "calculated" amount of diagnostic uncertainty.