The transcription factor GATA-3 is expressed in T helper 2 (T H 2) but not T H 1 cells and plays a critical role in T H 2 differentiation and allergic airway inflammation in vivo. Mice that lack the p50 subunit of nuclear factor κB (NF-κB) are unable to mount airway eosinophilic inflammation. We show here that this is not due to defects in T H 2 cell recruitment but due to the inability of the p50−/− mice to produce interleukin 4 (IL-4), IL-5 and IL-13: cytokines that play distinct roles in asthma pathogenesis. CD4+ T cells from p50−/− mice failed to induce Gata3 expression under T H 2-differentiating conditions but showed unimpaired T-bet expression and interferon γ (IFN-γ) production under T H 1-differentiating conditions. Inhibition of NF-κB activity prevented GATA-3 expression and T H 2 cytokine production in developing, but not committed, T H 2 cells. Our studies provide a molecular basis for the need for both T cell receptor and cytokine signaling for GATA-3 expression and, in turn, T H 2 differentiation.