Muscle fibrosis, the disruption, of functional parenchyma by stromal elements, is an often overlooked sequela of traumatic muscle injury, ageing, and congenital disease. The remarkable regenerative capacity of skeletal muscle is dependent on the interaction of myogenic progenitors and the same stromal connective tissue elements responsible for fibrosis generation and propagation. The coordination of effective therapeutic strategies to mitigate muscle fibrosis following injury requires a clear understanding of the prominent cellular progenitors, extracellular constituents, and signaling mechanisms involved in muscle healing. Recent studies have begun to elucidate the critical cellular processes that delineate physiologic regeneration and dysregulated healing resulting in muscle fibrosis. This review presents the salience of these novel findings in the context of the current treatment paradigms for muscle fibrosis.