Abstract: Lung cancer is the most commonly diagnosed malignancy and a leading cause of cancer death. Circulating tumor cells (CTCs) are tumor cells initially shed from the primary tumor that can spread to distant organs where they may trigger metastasis. CTCs have recently gained immense attention wherein they have been studied up to the molecular level. The clinical information carried by the CTCs offers great potential to guide treatment, reveal the mechanisms underlying metastasis, and to assess programmed cell death-ligand 1 (PD-L1) expression. In this review, we summarize the clinical significance of CTCs in the development of precision medicine for lung cancer. Moreover, the significance of CTCs and circulating-free DNA (cfDNA) is also discussed for potential clinical application in lung cancer, aiming to provide new insights into clinical detection and personalized therapy.