Gadd45β (growth arrest and DNA damage–inducible, β) is involved in cell cycle arrest, apoptosis, signal transduction and cell survival. In T cells, Gadd45b was rapidly induced by T cell receptor (TCR) and inflammatory signals. Deficiency of Gadd45β in CD4⁺ T cells impaired their responses to TCR stimulation or inflammatory cytokines. ERK, p38 and JNK activation were all substantially suppressed in Gadd45β-deficient CD4⁺ T cells. Cytokine production by Gadd45β-deficient CD4⁺ T cells was also impaired. Furthermore, Gadd45β mediated inflammatory cytokine production by dendritic cells, and Gadd45β-deficient mice showed an impaired T helper type 1 response during Listeria monocytogenes infection. Gadd45β is therefore a critical feedback regulator that perpetuates both cognate and inflammatory signals.