Cancers still consist an important health burden, due to high incidence and mortality. The discovery and clinical implementation of novel sensitive diagnostic markers could improve treatment outcomes. Circulating cell-free DNA (ccfDNA) offers great promise for the development of new molecular biomarkers. However, the analysis of ccfDNA methylation poses significant challenges due to ccfDNA fragmentation and low concentration in blood. Techniques, which have recently been developed for liquid biopsy studies, have been adapted to the detection of trace amounts of ccfDNA. This mini-review focuses on recent technological advances which allow the discovery of new sensitive and specific liquid biopsy cancer biomarkers based on DNA methylation detection.