DNA methylation, a key epigenetic mechanism, is orchestrated by DNA methyltransferases (DNMTs). DNMTs play vital role in human biology and pathophysiology and act as therapeutic targets in various diseases, particularly cancers. DNMTs are classified as DNMT1, DNMT3A, DNMT3B, and DNMT3L and each has distinct functions and are essential for tissue-specific gene expression, genomic stability, cellular differentiation, and the regulation of normal physiological functions. Aberrant DNA methylation is often associated with DNMTs dysregulation, resulting into complex interplay between global hypomethylation and gene-specific hypermethylation. These alterations significantly impact gene–gene networks and chromatin architecture, contributing to cancer initiation, progression, and metastasis. This chapter discusses the diverse roles of DNMTs in development, and oncogenesis, encompassing both hematological and solid tumors. With their pivotal role in various cancers, DNMTs have emerged as promising therapeutic targets. Therefore, this chapter provides an in-depth exploration of various DNMT inhibitors (DNMTis), including U.S. Food and Drug Administration (FDA)-approved drugs (azacitidine and decitabine), and elucidates their mechanisms of action and treatment strategies across different cancer types. This chapter also reviews current clinical trials focusing on second-generation DNMTi for treating various cancers, offering insights into the latest developments in the field. This chapter also addresses the current challenges associated with DNMT-targeted therapies, such as drug resistance and toxicity. This emphasizes the need for more specific inhibitors, improved delivery methods, and personalized therapeutic approaches based on individual methylation profiles. Overall, this comprehensive overview gives insights of the complex world of DNA methyltransferases and diseases, and their potential as therapeutic targets in the evolving landscape of epigenetic medicine.