Circulating cell-free DNA (cfDNA) methylation profiling enables minimally invasive cancer detection and monitoring. Among available methods, cfMeDIP-seq is a sensitive, scalable, bisulfite-free approach suitable for low-input cfDNA. This review summarizes its principles, comparative technologies, and clinical applications, including early detection, tumor classification, and minimal residual disease monitoring. Despite promising performance, challenges remain in standardization and validation, while emerging multi-omic integrations may further enhance its role in precision oncology.