What is it that limits how fast we can run, or how long we can row, cycle, or swim without tiring? What is exercise fatigue? One dares to say that not a single human being has not experienced those unpleasant feelings of physical exhaustion when taxed by some form of exercise. These effects are common and obvious, but, despite many years of research efforts, still unexplained. This book examines, from an historical perspective, the quest to decipher the underlying factors responsible for—and, indeed, simply the definition of—exercise fatigue. This story is told in the context of those researchers who have led this search for understanding. Some have been motivated by a search for an epiphany-like insight that would define the mechanisms by which living beings can be limited in their functional capacity, and some have sought this answer relative to socio-political issues surrounding human limitations in labor. Others have even been driven by a need to understand resistance to physical fatigue in humans engaged in war. Today, most such efforts to explain the nature and determinants of exercise fatigue involve optimizing performance in athletes and enhancing both the preventive and therapeutic health outcomes of exercise. The picture provided here is that of a multi-factorial nature of exercise fatigue, the determinants of which may be specific to the type, nature, and duration of the exercise involved. A more contemporary viewpoint, however, would suggest that the interaction between physiological factors may best define one’s ceiling of exercise performance. The implication of such a viewpoint would hold that factors defining exercise fatigue may be even more complicated than previously appreciated, meaning that this is a fascinating mystery waiting to be unraveled.