Expression of the transcription factor GATA-3 is strongly associated with T helper type 2 (T H 2) differentiation, but genetic evidence for its involvement in this process has been lacking. Here, we generated a conditional GATA-3-deficient mouse line. In vitro deletion of Gata3 diminished both interleukin 4 (IL-4)–dependent and IL-4-independent T H 2 cell differentiation; without GATA-3, T H 1 differentiation occurred in the absence of IL-12 and interferon-γ. Gata3 deletion limited the growth of T H 2 cells but not T H 1 cells. Deletion of Gata3 from established T H 2 cells abolished IL-5 and IL-13 but not IL-4 production. In vivo deletion of Gata3 using OX40-Cre eliminated T H 2 responses and allowed the development of interferon-γ-producing cells in mice infected with Nippostrongylus brasiliensis. Thus, GATA-3 serves as a principal switch in determining T H 1-T H 2 responses.