The histone acetyltransferase HBO1 is required for histone H3 lysine 14 acetylation and the expression of lineage-specific genes after gastrulation. However, the role of HBO1 during the development of specific tissues has been unclear. Now, Zoe Grant, Leigh Coultas, Anne Voss and colleagues use a tissue-specific conditional knockout of Hbo1 to assess its role during angiogenesis. They show that endothelial-specific deletion of Hbo1 impairs vessel growth in mouse retinas, both during normal development and during pathological vessel growth in response to oxygen-induced retinopathy. The researchers show that HBO1 is not required for endothelial cell (EC) proliferation or maintenance, nor does the lack of HBO1 increase EC apoptosis. Instead, using single-cell RNA sequencing, they reveal that migratory tip cells are enriched in HBO1-deficient retinas. Immunostaining determines that, although tip cells are specified normally in Hbo1 null retinas, they show evidence of migration defects and an accumulation of tip cell ECs at the sprouting front. Finally, chromatin immunoprecipitation and sequencing in human umbilical vein ECs shows that H3K14ac modifications are enriched at key vascular genes, such as PECAM1. Together, these data indicate that HBO1 promotes migratory tip cell behaviour during sprouting angiogenesis.