When muscle fibers are injured, skeletal muscle precursor cells proliferate and differentiate to regenerate and repair the injured muscle. The ability to regenerate skeletal muscle decreases with age, and Notch signaling is necessary for normal adult muscle repair. Conboy et al. now show that Notch also functions in the age-related decline in mouse skeletal muscle regeneration. Old and young muscles had equivalent numbers of muscle precursor cells, but cells from older mice were less able to induce the Notch ligand, Delta, and to activate Notch signaling in response to muscle injury. Forced activation of Notch-1 restored the regenerative potential of old muscle, whereas inhibition of Notch-1 impaired regeneration of young muscle.