Cells expressing the CD45-associated hematopoietic marker are predominantly present in the mammalian bone marrow (BM), but have recently been shown to also reside in the skeletal muscle and potentially participate in muscle repair. Despite the consistent observations, the specific relationship and potential migration of CD45+ cells in the BM versus CD45+ cells residing in the muscle remain unclear, in addition to any understanding of the factors that may regulate the trafficking of CD45+-derived BM cells to skeletal muscle upon i.v. transplantation. Here, transplantation of BM-derived cells fully replaced the CD45+ fraction of skeletal muscle, but gave rise to progenitor cells with distinct hematopoietic lineage capacity from CD45+ cells residing in the BM. Using transwell migration assays, a subset of BM cells was shown to migrate exclusively to mature skeletal muscle cells and not BM-derived stromal cells. Unlike migration of BM cells to stroma, myofiber induced migration of BM-derived cells was not affected by stromal-derived factor-1 (SDF-1) neutralization or CXCR4-blocking antibody, but could be reduced by addition of c-met-blocking antibody and augmented by hepatocyte growth factor (HGF), the putative ligand for c-met. We suggest that the BM compartment consists of a functionally complex population of CD45+ progenitors that includes a subset of HGF/c-met responsive cells capable of migration to skeletal muscle. This previously unappreciated basis for cellular tracking now aids in defining regulatory networks that distinguish the stem cell niche of the BM versus skeletal muscle microenvironments.