Abstract: The fusion gene of anaplastic lymphoma kinase (ALK) is the most common driver gene in non-small cell lung cancer (NSCLC) patients, apart from the epidermal growth factor receptor (EGFR) gene. NSCLC patients with positive ALK fusion genes can significantly benefit from targeted treatment with ALK tyrosine kinase inhibitors (TKIs), but ultimately develop TKI resistance. Exploring the resistance mechanism of ALK targeted therapy has always been a research focus. The resistance mechanisms of the first- and second-generation ALK TKIs have been reported multiple times, while the resistance mechanisms of the third-generation ALK TKIs lorlatinib still need further elaboration. This article will mainly focus on the resistance mechanism of third-generation ALK TKI lorlatinib from two aspects: ALK dependent mechanism (on-target resistance) and ALK independent mechanism (off-target resistance), including summarized the sensitivity of compound mutations to other TKIs after sequential treatment with lorlatinib and bypass activation pathway; the potential resistance mechanism of first-line treatment with lorlatinib; the research progress of the fourth generation ALK TKIs, as well as the significance of dynamic monitoring liquid biopsy in the treatment of lorlatinib.