Clinicians have suspected for hundreds of years that chronic activation of the immune system contributes to the development of cancer. However, the molecular mechanisms that mediate this precarious interplay are only now being elucidated. Recent reports have identified A20 as a crucial tumour suppressor in various lymphomas. A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signalling complexes at pro-inflammatory receptors. In this Review we summarize the evidence linking chronic inflammation with tumorigenesis and consider how A20 modulates inflammatory signalling cascades, thereby providing a mechanism to explain how deregulation of ubiquitylation can promote tumorigenesis.