High-mobility group protein box 1(HMGB1)is a ubiquitous highly conserved nuclear protein. Acting as a chromatin-binding factor, HMGB1 binds to DNA and plays an important role in stabilizing nucleosome formation, facilitating gene transcription, DNA repairing, inflammation, cell differentiation, and regulating the activity of steroid hormone receptors. Currently, HMGB1 is discovered to be related to development, progression, and targeted therapy of lung cancer, which makes it an attractive biomarker, and therapeutic target. This review aims to encapsulate the relationship between HMGB1 and lung cancer, suggesting that HMGB1 plays a pivotal role in initiation, development, invasion, metastasis, and prognosis of lung cancer.