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Human adult mesenchymal stem cells (MSCs) derived from bone marrow have the capacity to self-renew and to differentiate into a variety of cells and tissues. They can leave their niche to migrate to remote tissues where they play a critical role in angiogenesis, wound repair and tissue regeneration. A major goal in adult stem cell research is to define how MSC fate is controlled by the pericellular extracellular matrix (ECM) and soluble factors that largely constitute their tissue-specific niches. Defining crucial regulatory signals that control the fate and function of MSCs in vitro will contribute to the development of therapeutic strategies to improve tissue regeneration. The objective of this study was to investigate the molecular relationships between cell-ECM integrin receptors and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, which are crucial in modulating MSC expansion, recruitment, and differentiation towards a number of different cell lineages. This study reports that ECM-directed cross-talk between PDGFR-β and alpha5β1 integrin controls the migration of MSCs. Cell adhesion to fibronectin induced integrin alpha5β1-dependent phosphorylation of PDGFR-β in the absence of growth factor stimulation. Phosphorylated PDGFR-β co-immunoprecipitated with integrin alpha5 and co-localised with alpha5β1 in a transient tidemark of focal adhesions. Adhesion to fibronectin also strongly potentiated platelet-derived growth factor (PDGF)-BB-stimulated PDGFR-β phosphorylation, in an alpha5β1-dependent manner. PDGFR-β-activated phosphatidylinositol 3 ́-kinase (PI3-kinase) and Akt activity, actin reorganisation and cell migration were all regulated by fibronectin engagement of alpha5β1 integrin. This synergistic relationship between integrin alpha5β1 and PDGFR-β is a fundamental determinant of mesenchymal cell migration. Thus, fibronectin-rich matrices can prime PDGFR-β to recruit mesenchymal cells at sites of tissue remodelling.