Satellite cells, adult stem cells in skeletal muscle tissue, reside within a mechanically dynamic three-dimensional microenvironment. With each contraction-relaxation cycle, a satellite cell is expected to experience tensile, shear, and compressive stresses, and through cell-extracellular matrix interactions, also gauge the stiffness of the niche. Via mechanoreceptors, cells can sense these biophysical parameters of the niche, which serve to physically induce conformational changes that impact biomolecule activity, and thereby alter downstream signal transduction pathways and ultimately cell fate. An emerging body of literature supports the notion that myogenic cells, too, integrate biochemical factors together with biomechanical stresses and that this may serve to provide spatio-temporal control of cell fate in the complicated three-dimensional niche. Further, skeletal muscle regenerative medicine therapies are being improved by applying this fresh insight. In this focused chapter, the progression of skeletal muscle regeneration is dissected into a dynamic conversation between muscle progenitor cells and the mechanical properties of the extracellular matrix. The significance of biophysical regulation to myogenic repair is reinforced by the exaggerative influences of extrinsic mechanical stresses and the pathological implications of ECM dysregulation. Additional fundamental studies that further define the satellite cell biophysical environment in health, regeneration, aging, and disease may serve to close knowledge gaps and bolster skeletal muscle regenerative medicine.