Circulating tumor cells (CTCs) are critical in cancer metastasis, where tumor cells migrate through the bloodstream to other parts of the body. Recent technological advancements have enhanced understanding of CTC mechanisms, including DNA methylation, which regulates gene expression and chromosome stability. DNA methylation changes, such as global hypomethylation and locus-specific hypermethylation, are pivotal in carcinogenesis. This review explores how DNA methylation modifications in CTCs impact processes like epithelial-mesenchymal transition (EMT), immune evasion, and colonization. It also discusses clinical implications of these changes for cancer patients, highlighting the potential of DNA methylation as a biomarker for early detection, prognosis, and targeted therapies. CTCs are classified into epithelial, mesenchymal, and hybrid types, with some evading immune clearance to establish metastatic disease. CTCs face multiple challenges during dissemination, including adhesion, invasion, shear stress, and immune surveillance. Molecular markers like EpCAM are used to detect CTCs, but limitations exist, especially in EpCAM-negative cancers. Other markers, such as CD44, ALDH1, and EMT-related proteins, are also important. CTCs can form clusters, which have higher metastatic potential than individual cells. EMT is a key process in CTC survival and metastasis, involving changes in gene expression and signaling pathways. CTCs with stem-like properties are more resistant to therapy and can drive tumor relapse. CTC isolation and identification technologies are crucial for clinical applications, but challenges remain in obtaining sufficient CTCs for analysis. Advances in CTC research offer new insights into cancer biology and potential therapeutic strategies.Circulating tumor cells (CTCs) are critical in cancer metastasis, where tumor cells migrate through the bloodstream to other parts of the body. Recent technological advancements have enhanced understanding of CTC mechanisms, including DNA methylation, which regulates gene expression and chromosome stability. DNA methylation changes, such as global hypomethylation and locus-specific hypermethylation, are pivotal in carcinogenesis. This review explores how DNA methylation modifications in CTCs impact processes like epithelial-mesenchymal transition (EMT), immune evasion, and colonization. It also discusses clinical implications of these changes for cancer patients, highlighting the potential of DNA methylation as a biomarker for early detection, prognosis, and targeted therapies. CTCs are classified into epithelial, mesenchymal, and hybrid types, with some evading immune clearance to establish metastatic disease. CTCs face multiple challenges during dissemination, including adhesion, invasion, shear stress, and immune surveillance. Molecular markers like EpCAM are used to detect CTCs, but limitations exist, especially in EpCAM-negative cancers. Other markers, such as CD44, ALDH1, and EMT-related proteins, are also important. CTCs can form clusters, which have higher metastatic potential than individual cells. EMT is a key process in CTC survival and metastasis, involving changes in gene expression and signaling pathways. CTCs with stem-like properties are more resistant to therapy and can drive tumor relapse. CTC isolation and identification technologies are crucial for clinical applications, but challenges remain in obtaining sufficient CTCs for analysis. Advances in CTC research offer new insights into cancer biology and potential therapeutic strategies.