Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or β (PI5P4Kα and β) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and β in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K β and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A−/−, PIP4K2B+/−, and TP53−/− mice were viable and had a dramatic reduction in tumor formation compared to TP53−/− littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53. Display omitted •A subset of breast cancers express high levels of PI5P4Kα and/or β•PI5P4Ks play a critical role in HER2-positive and p53-defective breast cancers•Suppression of PI5P4K expression results in enhanced ROS and cellular senescence•PI5P4K inhibitors could be effective in treating cancers with mutations in TP53 Inhibition of a class of lipid kinases inhibits tumor growth in the absence of p53, revealing an opportunity to develop kinase inhibitors to treat a broad swath of human cancers.