Effective screening modalities are currently available for only a small subset of cancers, and they generally have suboptimal performance with complicated procedures. Therefore, there is an urgent need to develop simple, accurate, and non-invasive methods for early detection of cancers. Genetic and epigenetic alterations in plasma circulating cell-free DNA (cfDNA) have shown the potential to revolutionize methods of early detection of cancers and facilitate subsequent diagnosis to improve survival of patients. The medical interest in cfDNA assays has been inspired by emerging single- and multi-early detection of cancers studies. This review summarizes current technological and clinical advances, in the hopes of providing insights into the development and applications of cfDNA assays in various cancers and clinical scenarios. The key phases of clinical development of biomarkers are highlighted, and the future developments of cfDNA-based liquid biopsies in early detection of cancers are outlined. It is hoped that this study can boost the potential integration of cfDNA-based early detection of cancers into the current clinical workflow.