Each year, especially in the United States, young and middle aged men die from a variety of causes during or following intense physical exertion. For unknown reasons, death and disability as a consequence of physical effort are virtually unknown in women, despite the fact that they participate heavily in competitive sports. The most important complications of exhaustive exercise are shown in Table 1. Of these, rhabdomyolysis, especially if associated with exertional heat stroke, is one of the most devastating clinical illnesses that exists. The term rhabdomyolysis defines an injury to skeletal muscle cells of such severity that their contents leak into the circulation. The injury may be confirmed biochemically by demonstrating elevated concentrations of enzymes in serum that are specifically located in skeletal muscle cells (CK-MM, aldolase) or myoglobin. Myoglobin released into the circulation is filtered and excreted into the urine, so-called myoglobinuria. The latter invokes the risk of acute renal failure (pigment nephropathy). Exertional rhabdomyolysis is an exceptionally common event. It is probably experienced in mild form by everyone who has undergone some form of exercise training during their youth when it is expressed simply by stiff and tender muscles. If at that time someone happened to measure a serum CK value, it would be slightly to modestly elevated. Some of the most classic examples of frank exertional rhabdomyolysis occur among our most highly trained endurance runners. In the majority of cases, there is no history or other apparent evidence for myopathy before the event. In most who survive major episodes, subsequent muscle testing has shown no results that suggest a hereditary myopathy such as McArdle's Syndrome, carnitine palmityl transferase deficiency, or other myopathy. Because of this, it is assumed that any normal person may develop frank rhabdomyolysis provided the provocation is adequate. Provocative events consist of exhaustive exercise, especially when competitive, and particularly if the athlete musters his supreme effort to win during the last segment of a race. Hot or warm weather and a high relative humidity increase the risk enormously. Victims of this disorder often give a history that they continued to run despite cramping pain and dead legs. Some of them continue to run despite obvious disorientation and confusion. Observers commonly recall that victims appeared pallid or gray as if their skin vessels had become constricted as a result of a massive discharge of norepinephrine or alternatively, their cardiac output and peripheral circulation had failed. It seems that it is this last burst of effort that often provides the coup de grace , so that the patient develops major and widespread soft tissue injury and in some cases, heat stroke as an associated illness. It is unfortunate that the gravity of acute exertional rhabdomyolysis is so often unappreciated by physicians who initially provide care for these patients. Although the victim may collapse and appear to recover quickly, in some of these, potentially fatal metabolic acidosis, hyperkalemia, disseminated intravascular coagulation and the acute respiratory distress syndrome may appear during the following 24 hours. The syndrome of rhabdomyolysis is given little attention in the major textbooks of internal medicine. Perhaps this is one of the reasons why the gravity of the illness is so commonly unappreciated at the onset when appropriate identification and treatment of its complications could be life saving. There is strong evidence that training induces a degree of resistance to development of exertional rhabdomyolysis as well as exertional heat stroke. Some of this evidence will be reviewed, but with emphasis on the fact that even a highly trained athlete can still develop exertional rhabdomyolysis. Following the review of the physiological mechanisms that help forestall injury incident to exertion, several cases will be presented that will highlight some of the devastating complications of exercise.