Abstract: Advances in precision medicine are changing cancer therapeutics. The continuous exploration of molecular targets, and the emergence of new drugs and efficacy data have repeatedly saved lives of patients with cancer. With the dawn of precision medicine, therapeutic strategies for large cell neuroendocrine carcinoma of the lung (LCNEC), a relatively rare tumor, are actively being developed. In recent years, genomic and transcriptome analyses have revealed different subtypes of LCNEC, offering hope for personalized therapy. Reports suggest that targeted therapy may benefit patients with LCNEC carrying mutation in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and B-Raf proto-oncogene, serine/threonine kinase (BRAF^V600Ein particular). Additionally, novel directions have been provided for targeted therapy due to the upregulation of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (MTOR) signaling pathway and brain derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway, and antibody-drug-conjugate (ADC) technology. In terms of immunotherapy, programmed cell death protein-1 (PD-1) and programmed cell death protein-ligand 1 (PD-L1) inhibitors, as well as PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) double resistance in LCNEC has been studied. Immunotherapy may be considered as a posterior line of treatment in the absence of any other therapeutic regimens. Although long-term survival benefits of immunotherapy and targeted therapy have been reported in patients with LCNEC, prospective and large cohort studies are required for determination of their therapeutic value in LCNEC.