Investigations on extracellular matrix (ECM) and growth factor (GF) complexes have revealed an underappreciated phenomenon: they can either negate GF activity or generate synergistic signals for cell function, in particular mitogenesis. ECM and pericellular matrix molecules were first recognized to complex with GFs and regulate GF activity by the seminal observations that basic fibroblast growth factor (bFGF or FGF-2) required binding to a cell-surface heparin sulfate proteoglycan and to its authentic cell-surface receptor for biological activity (Klagsbrun and Baird, 1991; Yayon et al., 1991). Subsequently, numerous ECM–GF interactions that modulate GF activity were discovered; we have reviewed many of these findings (Macri et al., 2007).