Skeletal muscle owes its plasticity and ability to regenerate following severe injury to the resident somatic stem cells, termed satellite cells, of which a subset represent multipotent muscle stem cells (MuSCs). Adult MuSCs originate from mesoderm-derived somitic cells during embryonic development and are necessary for the maintenance and regeneration of skeletal muscle throughout life. In adult muscle, MuSCs reside under the basal lamina where extrinsic cues modulate their quiescence in resting conditions and activation in response to injury. The process of MuSC activation is highly regulated by the niche microenvironment, and perturbations that impact the MuSC-niche interaction can have deleterious effects on muscle regeneration. Here, we discuss the embryonic origin of skeletal muscle and MuSCs; the regulation of MuSC activation, self-renewal, and commitment; and myopathies that impact MuSC function.