Exercise intolerance results when a subject is unable to sustain a required work rate sufficiently long for the successful completion of the task. The ability to sustain muscular exercise depends in large part on the ability to transport oxygen to its site of utilization as the terminal oxidant of the mitochondrial electron transport chain. This requires a coordinated interaction of skeletal muscle energetics and cardiovascular and pulmonary responses to the task. This article considers the fundamentals of the normal operation of these systems and their patterns of response to particular stress profiles to provide a frame of reference for the normalcy of responses to exercise testing.