DNA hypomethylation is a common feature of carcinogenesis, often observed alongside hypermethylation of tumor suppressor genes. Initially overlooked, it has been confirmed through high-resolution genome-wide studies that DNA hypomethylation is a frequent companion to hypermethylation in cancer genomes. This review discusses the active demethylation process and its relationship to cancer stem cells, highlighting the dynamic nature of DNA methylation changes in cancer. DNA hypomethylation can be found early in carcinogenesis and is associated with tumor progression, often preceding aneuploidy. The biological significance and clinical relevance of DNA hypomethylation in cancer are accumulating evidence, and it is linked to both tumor progression and disease stage. The review also explores the tumor specificity of DNA hypomethylation, the dynamic nature of DNA methylation changes, and the potential causative role of DNA hypomethylation in carcinogenesis. Additionally, it discusses the role of nutrition and genetic sources of DNA methylation loss in cancer development and the impact of DNA hypomethylation on gene expression and chromosomal rearrangements. The cancer stem cell hypothesis is compatible with demethylation during carcinogenesis, and the mechanisms of DNA demethylation are still under investigation. Finally, the clinical implications of DNA hypomethylation in cancer diagnosis, prognosis, and treatment are discussed.DNA hypomethylation is a common feature of carcinogenesis, often observed alongside hypermethylation of tumor suppressor genes. Initially overlooked, it has been confirmed through high-resolution genome-wide studies that DNA hypomethylation is a frequent companion to hypermethylation in cancer genomes. This review discusses the active demethylation process and its relationship to cancer stem cells, highlighting the dynamic nature of DNA methylation changes in cancer. DNA hypomethylation can be found early in carcinogenesis and is associated with tumor progression, often preceding aneuploidy. The biological significance and clinical relevance of DNA hypomethylation in cancer are accumulating evidence, and it is linked to both tumor progression and disease stage. The review also explores the tumor specificity of DNA hypomethylation, the dynamic nature of DNA methylation changes, and the potential causative role of DNA hypomethylation in carcinogenesis. Additionally, it discusses the role of nutrition and genetic sources of DNA methylation loss in cancer development and the impact of DNA hypomethylation on gene expression and chromosomal rearrangements. The cancer stem cell hypothesis is compatible with demethylation during carcinogenesis, and the mechanisms of DNA demethylation are still under investigation. Finally, the clinical implications of DNA hypomethylation in cancer diagnosis, prognosis, and treatment are discussed.