The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is sufficient to induce asthma or atopic dermatitis-like phenotypes when selectively overexpressed in transgenic mice, or when driven by topical application of vitamin D3 or low-calcemic analogues. Although T and B cells have been reported to be dispensable for the TSLP-induced inflammation in these models, little is known about the downstream pathways or additional cell types involved in the inflammatory response driven by TSLP. To characterize the downstream effects of TSLP in vivo, we examined the effects of exogenous administration of TSLP protein to wild-type and genetically deficient mice. TSLP induced a systemic Th2 inflammatory response characterized by increased circulating IgE and IgG1 as well as increased draining lymph node size and cellularity, Th2 cytokine production in draining lymph node cultures, inflammatory cell infiltrates, epithelial hyperplasia, subcuticular fibrosis, and up-regulated Th2 cytokine and chemokine messages in the skin. Responses to TSLP in various genetically deficient mice demonstrated T cells and eosinophils were required, whereas mast cells and TNF-alpha were dispensable. TSLP-induced responses were significantly, but not completely reduced in IL-4- and IL-13-deficient mice. These results shed light on the pathways and cell types involved in TSLP-induced inflammation.