SETD2-dependent histone H3 lysine 36 trimethylation (H3K36me3) plays a central role in both maintaining genome stability and in suppressing tumorigenesis, and is frequently depleted in particular cancer types. We find this histone mark plays an important role in promoting homologous recombination (HR) repair of DNA double-strand breaks. Further, H3K36me3 also performs an essential role in facilitating DNA replication following WEE1 kinase inhibition, through promoting efficient deoxyribonucleotide synthesis. Accordingly, H3K36me3-deficient cancers can be specifically targeted using the WEE1 inhibitor, AZD1775, resulting in replicative catastrophe and cell death. The use of AZD1775 to target H3K36me3-deficient cancers is now in clinical trials. Mechanistic insights into the targeting of H3K36me3-deficient cancers with AZD1775 and its implications will be presented.