Allergic asthma, a major cause of morbidity and leading cause of hospitalizations, is an inflammatory disease orchestrated by T helper cells and characterized by lung migration of eosinophils, important asthma effector cells. Lung migration of inflammatory cells requires, among other events, chemokine receptor transduction of lung-produced inflammatory chemokines. Despite the widespread prevalence of this disease, the molecular mechanisms regulating chemokine production and receptor regulation in asthma are poorly understood. Previous work from our laboratory demonstrated that -arrestin-2 positively regulates the development of allergic airway disease in a mouse model, in part, through positive regulation of T-lymphocyte chemotaxis to the lung. However, -arrestin-2 is expressed in many cell types, including other hematopoietic cells and lung structural cells, which are involved in the development and manifestation of allergic airway disease. To determine the cell types required for -arrestin-2-dependent allergic inflammation, we generated bone marrow chimera mice. Using the ovalbumin murine model of allergic airway disease we show that eosinophilic and lymphocytic inflammation is restored in chimeric mice with expression of -arrestin-2 exclusively on hematopoietic-derived cell types. In contrast, airway hyperresponsiveness is dependent on expression of -arrestin-2 on structural cells. In summary, our data demonstrate expression of -arrestin-2 in at least two divergent cell types contributes to the pathogenesis of allergic airway disease.