Liquid biopsy provides a minimally-invasive alternative to solid tissue biopsy for assessing tumor-derived molecules such as circulating tumor DNA (ctDNA). Detection and characterization of ctDNA in the blood shows promise in early cancer screening and diagnosis, and has prognostic value for risk-stratification at all stages of disease. ctDNA can also be used for minimally-invasive tumor genotyping, treatment monitoring, and pre-clinical detection of minimal residual disease and recurrence. Although once predicted as a panacea for these applications, the clinical implementation of ctDNA assays has met with significant technical hurdles. Moreover, poorly-understood biological mechanisms and a lack of standardized methods contribute to measurement variability. The work that follows is intended to (1) highlight the need for a deeper understanding of the biological underpinnings of ctDNA release and kinetics, and (2) test the limits of patient-specific and patient-agnostic ctDNA detection technologies in the clinical setting.