Muscle glucose transport activity increases with an acute bout of exercise, a process that is accomplished by the translocation of glucose transporters to the plasma membrane. This process remains intact in the skeletal muscle of individuals with insulin resistance and type 2 diabetes mellitus (T2DM). Exercise training is, therefore, an important cornerstone in the management of individuals with T2DM. However, the acute systemic glucose responses to carbohydrate ingestion are often augmented during the early recovery period from exercise, despite increased glucose uptake into skeletal muscle. Accordingly, the first aim of this review is to summarize the knowledge associated with insulin action and glucose uptake in skeletal muscle and apply these to explain the disparate responses between systemic and localized glucose responses post-exercise. Herein, the importance of muscle glycogen depletion and the key glucoregulatory hormones will be discussed. Glucose uptake can also be stimulated independently by hypoxia; therefore, hypoxic training presents as an emerging method for enhancing the effects of exercise on glucose regulation. Thus, the second aim of this review is to discuss the potential for systemic hypoxia to enhance the effects of exercise on glucose regulation.