Cell-free DNA (cfDNA) is a promising, noninvasive tumor ‘liquid biopsy’ with quantitative and qualitative significance. Circulating cfDNA levels are raised in cancer patients and cfDNA exhibits genetic and epigenetic changes found in the underlying tumor. In lung cancer patients, cfDNA levels and tumor-associated genetic and epigenetic changes have been assessed as diagnostic, prognostic and predictive biomarkers. To date, many small studies have been reported with contradictory results. Their interpretation is hampered by differences in methodology and the selection of patients and controls. The treatment of lung cancer is increasingly guided by molecular subtyping, but access to tumor tissue is limited and cfDNA represents an attractive alternative. Moreover, repeated sampling of cfDNA is feasible and cfDNA may be more representative of tumor heterogeneity than a small biopsy sample. However, the establishment of robust and standardized protocols for blood sampling, processing, storage, DNA extraction and analysis are required before cfDNA biomarkers can be utilized in clinical practice.