Proinflammatory cytokines such as TNF, IL-1β and IL-6 produced by tumor-associated macrophages can support tumor growth and metastasis. Receptor signaling from inflammatory stimulation leads to K63-linked polyubiquitination of the protein kinase Tak1 and activation through autophosphorylation. Activated Tak1, in turn, phosphorylates IKK, leading to downstream activation of NF-κB-regulated genes. The E3 ligase Itch is a regulator of inflammation and the deubiquitinating enzyme Cyld regulates various human cancers and cytokine secretion in inflammatory cells. Cyld has been shown to cleave the K63-linked polyubiquitin chain on Tak1. Now, Venuprasad and colleagues show that Itch and Cyld work in concert to regulate the inflammatory response. They find that Itch or Cyld deficiency leads to growth and metastasis of lung carcinomas in inoculated mice, and the tumors have higher levels of TNF, IL-1β and IL-6. The authors show that Itch and Cyld form a complex that is able to remove the K63-linked polyubiquitin chain and exchange it for a K48-linked polyubiquitin chain, leading to proteasomal-mediated degradation of Tak1. In Itch- or Cyld-deficient macrophages, there was prolonged Tak1 activation and increased secretion of proinflammatory cytokines. Additional data indicate that the deubiquitinating activity of Cyld and its association with Itch are essential for terminating the Tak1-mediated inflammatory response. As chronic cytokine production has been linked to tumor progression, Tak1 could be a new target for cancer treatment. (Nat. Immunol. 12, 1176–1183, 2011)