The atypical protein kinase C isoform, ζPKC, has been implicated in the control of extracellular signal‐regulated kinase (ERK) and nuclear factor (NF)‐κB pathways. Recent evidence from ζPKC knock‐out mice demonstrates that this kinase is important for NF‐κB transcriptional activity but not for ERK activation in embryonic fibroblasts. The lack of ζPKC produces in mice a number of alterations in the development of secondary lymphoid tissues that could be accounted for, at least in part, by defects in B‐cell function. Here, we present evidence that the loss of ζPKC selectively impairs signaling through the B‐cell receptor, resulting in inhibition of cell proliferation and survival, as well as defects in the activation of ERK and the transcription of NF‐κB‐dependent genes. Furthermore, ζPKC−/− mice are unable to mount an optimal T‐cell‐dependent immune response. Collectively, these results genetically establish a critical role for ζPKC in B‐cell function in vitro and in vivo.