5-Methylcytosine (5mC) is the most abundant epigenetic mark in DNA regulating gene expression and influencing crucial cellular processes. Aberrant DNA methylation is involved in pathogenesis of human malignancies. Detection of cancer-specific methylation patterns in cell-free DNA (cfDNA) is a promising approach for development of minimally invasive, liquid biopsy assays. Most of methylation sequencing methods are based on bisulfite treatment that causes an extensive DNA damage, therefore are not ideal for analysis of minute amount of cfDNA. Unfortunately, technological limitations affect whole-genome methylation analysis of cfDNA. During the course of this project, we developed and validated novel approaches addressing the most important drawbacks of currently available technologies. First, we developed and validated enrichment-based cfMeSeal approach by combining enzymatic and chemical labelling for cost-effective 5mC sequencing in cfDNA. Second, we designed and developed a bisulfite-free method, Tet-assisted Pyridine Borane Sequencing (TAPS) for base-resolution 5mC sequencing. We demonstrated that TAPS is a mild reaction and outperforms bisulfite sequencing (BS-seq) at many aspects including improved sequence quality, better mapping statistics and direct conversion of modified sites. Finally, we confirmed that TAPS can be applied for cfDNA methylation sequencing and provides comprehensive information of cfDNA methylation and fragmentation. Information gained from cfDNA TAPS sequencing enables detection of hepatocellular carcinoma and pancreatic cancer with high accuracy. Together, we demonstrated that newly developed sequencing tools can outperform existing technologies and facilitate comprehensive cfDNA methylation sequencing and provide multidimensional information about cfDNA with high cancer predictive potential.