Qualitative and quantitative analysis of circulating cell-free DNA (cfDNA) is an emerging non-invasive blood biomarker utilized to assess tumor progression and to evaluate prognosis, diagnosis and response to treatment. There is a need to develop cfDNA biomarkers to avoid complex risk-prone biopsy procedures for primary or metastatic tumors. Given the challenges associated with inter- and intra-tumor heterogeneity, the implementation of genome-wide cfDNA analysis will become an important avenue to understand tumor progression and therapeutic settings, not only for predominant, but also for under-represented tumor subclones with specific genomic aberrations. We summarize the latest publications in cfDNA analysis, including a metric analysis of clinical trials and new high-throughput technology applied to cfDNA analysis in clinical oncology.