USP22 is a deubiquitinating enzyme that has previously been identified as a component of the SAGA transcriptional coactivator complex. Usp22 is upregulated in many forms of aggressive cancers and Usp22-null mutations are embryonic lethal in mice, but the role of this factor during development is poorly understood. Now, Sharon Dent and colleagues reveal that USP22 is essential for vascularisation of the placenta. Using transcriptomic analyses, the authors identify defects in TGFβ and receptor tyrosine kinase signalling in Usp22-null mutant placentas. They show that mutant placentas have defects in angiogenesis and vessel migration, increased endothelial marker expression and decreased expression of perivascular cell (including pericyte) markers. The researchers use an in vitro culture system to discriminate between the function of USP22 in induced endothelial cells and pericytes. They show that USP22 is required for propagation of induced endothelial cells, but dispensable for their specification, whereas it is necessary for pericyte differentiation. Furthermore, Usp22 mutant induced endothelial cells have a reduced migratory capacity — which is consistent with in vivo data. This study identifies USP22 as an indispensable regulator of signal integration in developing endothelial cells and pericytes, and may provide new insights into the highly aggressive nature of tumours that overexpress Usp22.