The purpose of our article was to review the major physiological limitations to endurance exercise. Though the physiological mechanisms regulating endurance performance are quite complex, the main factors limiting prolonged exercise have a straightforward interpretation. To continue exercise for extended durations, sustained muscle contraction must be maintained and is dependent on the continuous provision of both oxygen and fuel. Although each of the physiological limitations is modifiable through endurance training, it is important to recognize that genetic factors play a tremendous role in the trainability of these limitations and their capacity. It is therefore critical for coaches, fitness instructors, and personal trainers to recognize the all of the physiological components limiting endurance performance as they design exercise programs to improve endurance capacity.