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A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling. This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB. The gumby mutation in mice is associated with lethal angiogenic defects in the embryo. Here Sabine Cordes and colleagues show that the gumby gene encodes a deubiquitinase that specifically recognizes and cleaves linear ubiquitin chains and they implicate linear (de)ubiquitination in Wnt signalling and angiogenesis. In humans, gumby-containing deletions on chromosome 5p15.2 are associated with mental retardation and craniofacial anomalies observed in cri du chat syndrome (CdCS) patients. Although not the only gene deleted, gumby might contribute to some CdCS symptoms via its effects on linear deubiquitination. This work identifies gumby and the pathways regulating the deubiquitination–ubiquitination balance as of possible relevance to antiangiogenic therapies.