Cysteinyl leukotrienes and the T helper (Th)-2 cytokines IL-5 and IL-13 directly modulate human airway smooth muscle functions such as contraction and proliferation. We studied the effects of other lipid mediators involved in asthma pathophysiology such as prostaglandin D₂ (PGD₂), lipoxin, and isoprostanes, and the cytokines, IL-5, IL-4, and IL-13 on human airway smooth muscle cell migration. Chemotaxis and chemokinesis of cultured airway smooth muscle cells from humans without asthma (second to fifth passages, n = 6) were studied using collagen-I–coated polycarbonate membranes in Transwell culture plates. Receptor expression and kinase activation were studied by flow cytometry, polymerase chain reaction, and Western blotting techniques. In contrast to LTE₄- stimulated (10⁻⁶ M) chemokinesis and LTE₄-primed migration toward platelet-derived growth factor (PDGF), isoprostane 15-F_2t-IsoP, and IL-5 were neither chemotactic nor chemokinetic. PGD₂ (10⁻¹⁰–10⁻⁶ M) was a chemoattractant and primed migration toward PDGF through the DP₂/CRTh₂ receptor. Although airway smooth muscle cells did not express the lipoxin A₄ cognate receptor, LTE₄-primed migration toward PDGF was blocked by lipoxin A₄ (10⁻⁶ M), suggesting that this is mediated through CysLT₁R antagonism. IL-13 (10 ng/ml), but not IL-4 (0.1–100 ng/ml), augmented migration toward PDGF. This was associated with increased Src-kinase phosphorylation and up-regulation of PDGF-α and -β receptors, and was attenuated by IL-13Rα– and IL-4Rα–neutralizing antibodies, an Src-kinase antagonist (PP1, 3 μM), a CysLT₁R antagonist, montelukast (10⁻⁶ M), and by lipoxin A₄ (10⁻⁶ M). PGD₂ and IL-13 promote human airway smooth muscle migration. IL-13 can promote airway smooth muscle migration through Src-kinase and leukotriene-dependent pathways. This may contribute to the accumulation of smooth muscle cells in remodeled airway submucosa.