Glucose uptake into muscle and its subsequent storage as glycogen is a crucial factor in energy homeostasis in skeletal muscle. This process is stimulated acutely by insulin and is impaired in both insulin-resistant states and in type 2 diabetes mellitus. A signalling pathway involving protein kinase B and glycogen synthase kinase 3 seems certain to have a key role in stimulating glycogen synthesis but other signalling pathways also contribute, including a rapamycin-sensitive pathway stimulated by amino acids. Although glycogen synthesis is one of the classical insulin-regulated pathways, it is also regulated in an insulin-independent manner; for example glycogen synthesis in muscle is stimulated significantly after strenuous exercise, with much of this stimulation being independent of the involvement of insulin. Evidence suggests that glucose and the glycogen content of the muscle have a key role in this stimulation but the molecular mechanism has yet to be fully explained.