NK T cells recognize glycolipid Ags such as alpha-galactosylceramide (alpha-GalCer) presented by the MHC class I-like molecule CD1d. In this paper we have studied the in vivo effects of alpha-GalCer on the generation of adaptive immune responses. Treatment of mice with alpha-GalCer resulted in rapid activation of NK T cells and production of the cytokines IL-4 and IFN-gamma. However, after this initial stimulation, NK T cells became polarized for the production of IL-4. Further, as soon as 6 days after alpha-GalCer injection, a marked increase in serum IgE levels was observed. Administration of alpha-GalCer at the time of priming of mice with protein Ag resulted in the generation of Ag-specific Th2 cells and a profound increase in the production of IgE. Collectively, these findings indicate that alpha-GalCer may be useful for modulating immune responses toward a Th2 phenotype during prophylaxis and therapy.