Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increase in the activities of Src-family and Syk/Zap-70-family kinases  . These activated kinases then induce the tyrosine phosphorylation of multiple intracellular proteins, eventually leading to T-cell activation. One of the prominent substrates for these kinases is the adaptor protein Cbl  and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70  . Cbl-b, a homologue of Cbl, is widely expressed in many tissues and cells including hematopoietic cells  . Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors  . The role of Cbl-b is unclear, however. Here, we show that overexpression of Cbl-b in T cells induced the constitutive activation of the transcription factor nuclear factor of activated T cells (NFAT). A loss-of-function mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-70 and nearly completely abrogated the Cbl-b-mediated activation of NFAT. Unlike the proposed role of Cbl as a negative regulator, our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling, most likely via a direct interaction with the upstream kinase Zap-70.