Precision oncology is predicated upon the ability to detect specific actionable 
genomic alterations and to monitor their adaptive evolution during treatment to 
counter resistance. Because of spatial and temporal heterogeneity and 
comorbidities associated with obtaining tumor tissues, especially in the case of 
metastatic disease, traditional methods for tumor sampling are impractical for 
this application. Known to be present in the blood of cancer patients for 
decades, cell-free DNA (cfDNA) is beginning to inform on tumor genetics, tumor 
burden, and mechanisms of progression and drug resistance. This substrate is 
amenable for inexpensive noninvasive testing and thus presents a viable approach 
to serial sampling for screening and monitoring tumor progression. The 
fragmentation, low yield, and variable admixture of normal DNA present 
formidable technical challenges for realization of this potential. This review 
summarizes the history of cfDNA discovery, its biological properties, and 
explores emerging technologies for clinically relevant sequence-based analysis 
of cfDNA in cancer patients. Molecular barcoding (or Unique Molecular 
Identifier, UMI)-based methods currently appear to offer an optimal balance 
between sensitivity, flexibility, and cost and constitute a promising approach 
for clinically relevant assays for near real-time monitoring of 
treatment-induced mutational adaptations to guide evidence-based precision 
oncology. Mol Cancer Res; 14(10); 898-908. ©2016 AACR.