Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration. This Review discusses cumulative data on multiple treatment modalities with a particular focus on recent advances in molecularly targeted therapies in subtypes of patients with leptomeningeal metastasis from NSCLC. Future research is needed to further understand the biology of leptomeningeal metastasis and the mechanisms of resistance to treatment.