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Simple Summary: Liquid biopsies provide a non-invasive means to diagnose and profile tumors when tissue is not available. Sequence-based analysis of cell-free DNA (cfDNA) is frequently used to characterize genomic alterations, with a focus on driver mutations or mechanisms of acquired therapy resistance. However, the epigenome of cfDNA also contains additional information about the tumor, which might open new possibilities for clinical applications. Recent highlighted publications are reviewed on the analysis of fragmentation, epigenomic alterations, as well as nucleosome modifications using cfDNA in various cancers. The potential, challenges, and future directions of genomic and epigenomic analysis of cfDNA in oncology are discussed. Cell-free DNA (cfDNA) analysis using liquid biopsies is a non-invasive method to gain insights into the biology, therapy response, mechanisms of acquired resistance and therapy escape of various tumors. While it is well established that individual cancer treatment options can be adjusted by panel next-generation sequencing (NGS)-based evaluation of driver mutations in cfDNA, emerging research additionally explores the value of deep characterization of tumor cfDNA genomics and fragmentomics as well as nucleosome modifications (chromatin structure), and methylation patterns (epigenomics) for comprehensive and multi-modal assessment of cfDNA. These tools have the potential to improve disease monitoring, increase the sensitivity of minimal residual disease identification, and detection of cancers at earlier stages. Recent progress in emerging technologies of cfDNA analysis is summarized, the added potential clinical value is highlighted, strengths and limitations are identified and compared with conventional targeted NGS analysis, and current challenges and future directions are discussed. [ABSTRACT FROM AUTHOR]