I B kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NFB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKK in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKK , but not IKK , is required for Tpl2 activation. Moreover, this novel function of IKK appears to involve phosphorylation and degradation of the Tpl2 inhibitor NFB1/p105. These findings suggest that IKK exerts its immune-regulatory functions by targeting different downstream signaling pathways.