COP1 is an E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation. Although originally identified in a light signalling pathway in plants, biochemical studies have identified putative targets of mammalian COP1 with relevant roles in tumorigenesis, including the oncoproteins JUN and ETV family members, as well as the p53 tumour suppressor. Recent genetic studies have shown that COP1 deficiency leads to spontaneous tumour formation in mice, and have identified mutations in COP1 and its substrates in various human cancers. These findings add to our growing appreciation of the roles for E3 ligases in cancer.