The Ubc13 E2 ubiquitin-conjugating enzyme is key in the process of 'tagging' target proteins with lysine 63-linked polyubiquitin chains, which are essential for the transmission of immune receptor signals culminating in activation of the transcription factor NF-kappaB. Here we demonstrate that conditional ablation of Ubc13 resulted in defective B cell development and in impaired B cell and macrophage activation. In response to all tested stimuli except tumor necrosis factor, Ubc13-deficient cells showed almost normal NF-kappaB activation but considerably impaired activation of mitogen-activated protein kinase. Ubc13-induced activation of mitogen-activated protein kinase required, at least in part, ubiquitination of the adaptor protein IKKgamma. These results show that Ubc13 is key in the mammalian immune response.