Macrophages from Tpl2 knockout (Tpl2−/−) mice exhibit a defect in ERK activation by lipopolysaccharide (LPS). This impairs the nucleocytoplasmic transport of the tumor necrosis factor α (TNF‐α) mRNA and prevents the induction of TNF‐α by LPS. As a result, Tpl2−/− mice are resistant to LPS/d‐galactosamine‐induced shock. We demonstrate that Tpl2 is essential for ERK signals transduced by members of the TNF receptor superfamily, such as CD40 and the TNF receptor 1. Thus, ERK activation was impaired in Tpl2−/− B cells and macrophages stimulated with agonistic CD40 antibody or TNF‐α, whereas the induction of other mitogen‐activated protein kinases, such as JNK and p38, and the activation of NF‐κB were unaffected. Tpl2 was recruited to a CD40/TRAF6 complex in response to CD40 stimulation. Moreover, TRAF6, which when overexpressed activates ERK, failed to do so in Tpl2−/− cells. The selective signaling defect resulting from the inactivation of Tpl2 allowed us to demonstrate that CD40‐mediated ERK activation contributes to immunoglobulin production but is not essential for B‐cell proliferation.