Muscle regeneration is a complex process requiring the coordinated interaction between the myogenic progenitor cells or satellite cells, growth factors, cytokines, inflammatory components, vascular components and the extracellular matrix (ECM). Previous studies have elegantly described the physiological modulation of the regenerative process in response to muscle injury, but the molecular response that characterizes stages of the repair process remains ill-defined. The recent completion of the Human and Mouse Genome Projects and the advent of technologies such as high-density oligonucleotide array analysis facilitate an expanded analysis of complex processes such as muscle regeneration. In the present study, we define cellular and molecular events that characterize stages of muscle injury and regeneration. Utilization of transcriptional profiling strategies revealed coordinated expression of growth factors [i.e., Tgfb1, Igf1, Egf, chemokine (C-C motif) ligand 6 and 7], the fetal myogenic program (Myod1, Myf5, Myf6), and the biomatrix (procollagen genes, Mmp3, Mmp9, biglycan, periostin) during muscle regeneration. Corroboration of the transcriptional profiling analysis included quantitative real-time RT-PCR and in situ hybridization analyses of selected candidate genes. In situ hybridization studies for periostin [osteoblast-specific factor 2 (fasciclin I-like)] and biglycan revealed that these genes are restricted to mesenchymal derivatives during embryogenesis and are significantly regulated during regeneration of the injured hindlimb skeletal muscle. We conclude that muscle regeneration is a complex process that requires the coordinated modulation of the inflammatory response, myogenic progenitor cells, growth factors, and ECM for complete restoration of muscle architecture.