Due to its mass, skeletal muscle is the major site of glucose uptake and an important tissue in the development of type 2 diabetes (T2D). Muscles of patients with T2D are affected with insulin resistance and mitochondrial dysfunction, which result in impaired glucose and fatty acid metabolism. A well-established method of managing the muscle metabolic defects occurring in T2D is physical exercise. During exercise, muscles contract and secrete factors called myokines which can act in an autocrine/paracrine fashion to improve muscle energy metabolism. In patients with T2D, plasma levels as well as muscle levels (mRNA and protein) of some myokines are upregulated, while others are downregulated. The signalling pathways of certain myokines are also altered in skeletal muscle of patients with T2D. Taken together, these findings suggest that myokine secretion is an important factor contributing to the development of muscle metabolic defects during T2D. It is also of interest considering that lack of physical activity is closely linked to the occurrence of this disease. The causal relationships between sedentary behavior, factors secreted by skeletal muscle at rest and during contraction and the development of T2D remain to be elucidated. Many myokines shown to influence muscle energy metabolism still have not been characterized in the context of T2D in skeletal muscle specifically. The purpose of this review is to highlight what is known and what remains to be determined regarding myokine secretion in patients with T2D to uncover potential therapeutic targets for the management of this disease.