Development of the extracellular matrix is a critical feature of alveolar formation and actively involves pulmonary interstitial fibroblasts. The elastic fiber network is an interconnected system of load-bearing fibers that also influences the behavior of adjacent cells, particularly the interstitial lung fibroblasts (LF). We hypothesized that discrete domains of fibrillins-1 and -2, interact with LF integrins and direct their migration in the presence of platelet-derived growth factor (PDGF)-A. Surfaces coated with recombinant peptides lacking or including an arginine-glycine-aspartic acid (RGD) motif were used to study LF migration across porous filters and on protein-coated glass. Exon 24 of fibrillin-2 (Fib2 24), which encodes for a RGD-containing transforming growth factor-beta-binding (TB) domain stimulated migration with greater directional persistence and more effectively stimulated trans-filter migration at low concentrations. Exons 36-44 of fibrillin-1 (Fib1 36-44), which include epidermal growth factor (EGF)-like domains and a RGD-containing TB domain induce more lamlellipodia and more widespread remodeling of the leading edge, resulting in greater migration velocity than did Fib2 24. Distinct structural features in regions that surround the RGD-motifs may differentially regulate how the PDGF-receptor-alpha promotes integrin distribution and actin filament remodeling at the cells leading edge. Understanding how fibrillins regulate LF migration may help elucidate how the elastic fiber system could be restored as an interconnected unit, which fails to occur in emphysematous lungs.