In the last decade, large-scale genomic studies in patients with hematologic malignancies identified recurrent somatic alterations in epigenetic modifier genes. Among these, the DNA methyltransferase has emerged as one of the most frequently mutated genes in adult myeloid as well as lymphoid malignancies and in clonal hematopoiesis. In this review, we discuss recent advances in our understanding of the biochemical and structural consequences of mutations on DNA methylation catalysis and binding interactions and summarize their effects on epigenetic patterns and gene expression changes implicated in the pathogenesis of hematologic malignancies. We then review the role played by mutant in clonal hematopoiesis, accompanied by its effect on immune cell function and inflammatory responses. Finally, we discuss how this knowledge informs therapeutic approaches for hematologic malignancies with mutant .