Lung cancer maintains a high morbidity and mortality rate globally despite significant advancements in detection and therapy in the era of precision medicine. Excisional biopsy and histopathologic analysis, the current gold standards for lung cancer diagnosis, are intrusive and intrinsically confined to evaluating the limited amount of tissue that could be physically extracted. Furthermore, due to tumor heterogeneity or low tumor cellularity, lung biopsy is prone to producing misleading results. Unfortunately, there has been no major breakthrough in tumor biomarkers with high specificity and sensitivity, particularly for early-stage lung cancer. Liquid biopsy, an innovative method for the assessment of cancer, has been considered a feasible auxiliary tool for the diagnosis, treatment and prognosis of lung cancer. Circulating tumor DNA (ctDNA), the main target of liquid biopsy, has emerged as one of the most sensitive tools for monitoring tumor molecular processes. Herein, this review focuses on tumor heterogeneity to elucidate the superiority of liquid biopsy and retrospectively discuss its evolution. We systematically elaborate ctDNA biological characteristics, introduce methods for ctDNA detection, and provide a summary of how ctDNA analysis has been used in patients with lung cancer. Finally, we cover the drawbacks of ctDNA analysis in current applications and highlight its promising future in lung cancer.Copyright © 2023. Published by Elsevier B.V.