Diabetes is a global epidemic, of which type 2 diabetes makes up the majority of cases. Nonetheless, for some individuals, type 2 diabetes is eminently preventable and treatable via lifestyle interventions. Glucose uptake into skeletal muscle increases during and in recovery from exercise, with exercise effective at controlling glucose homeostasis in individuals with type 2 diabetes. Furthermore, acute, and chronic exercise sensitizes skeletal muscle to insulin. A complex network of signals converge and interact to regulate glucose metabolism and insulin sensitivity in response to exercise. Numerous forms of post-translational modifications (e.g. phosphorylation, ubiquitination, acetylation, ribosylation and more) are regulated by exercise. Here we review the current state-of-the-art of the role of post-translational modifications in transducing exercise-induced signals to modulate glucose uptake and insulin sensitivity within skeletal muscle. Furthermore, we consider emerging evidence for non-canonical signaling in the control of glucose homeostasis and the potential for regulation by exercise. While exercise is clearly an effective intervention to reduce glycemia and improve insulin sensitivity, the insulin- and exercise-sensitive signaling networks orchestrating this biology are not fully clarified. Elucidation of the complex proteome-wide interactions between post-translational modifications and the associated functional implications will identify mechanisms by which exercise regulates glucose homeostasis and insulin sensitivity. In doing so, this knowledge should illuminate novel therapeutic targets to enhance insulin sensitivity for the clinical management of type 2 diabetes.