Individualized therapy for advanced NSCLC is a tailor-made treatment based on the molecular biological characteristics of each patient’s tumor, combined with clinical features. It should be noted that this treatment is under the guidance of evidence-based medicine, does not violate the basic principles of standardized treatment, and takes into account the tumor heterogeneity of a class or a certain individual patient, and rationally carries out the first-, second-, or third-line chemotherapy/biological targeting therapy. First of all, individualized treatment of advanced NSCLC must be closely integrated with the clinical characteristics of patients. Numerous studies have confirmed that patients’ age, gender, ECOG behavioral status score, histological type, metastatic site of the tumor, and whether or not they are smokers, etc., may affect patients’ prognosis, especially when advanced NSCLC enters the era of biologic-targeted therapies, and the impact of these tumor heterogeneities on the therapeutic efficacy has been very significant. Second, individualized treatment of advanced NSCLC must try to reflect the molecular biology of the patient’s tumor. Among the relevant molecular biological markers affecting the efficacy of chemotherapy, some studies have shown that the expression level of tumor nucleotide excision repair cross-complenting group 1 (ERCC1) is closely related to the efficacy of platinum-based drugs on NSCLC, while ribonucleotide reductase regulator 1 (ribonucleotide reductase regulator 1) is closely related to the efficacy of platinum-based drugs on NSCLC. ribonucleotide reductase M1 (RRM1) was closely related to the efficacy of gemcitabine in NSCLC, and the expression level of thymidylate synthetase (TS) may explain the difference in the efficacy of TS drugs in different tumor histological types. Among the relevant molecular biomarkers affecting the efficacy of biologically targeted drugs, the copy number of epidermal growth factor receptor (EGFR), the mutation status of EGFR, and the mutation status of K-ras may affect the efficacy of drugs targeting the EGFR signaling pathway. Furthermore, when it is difficult to obtain a more comprehensive molecular biological profile in the individualized treatment of advanced NSCLC, the correlation between the clinical characteristics of the patient and the molecular biological profile should be taken into account, e.g., non-smoking female adenocarcinomas have a high EGFR mutation rate of up to 60% and a low K-ras mutation rate of more than wild-type; whereas, TS expression is significantly higher in squamous than in adenocarcinomas, and significantly higher in highly malignant than in less TS expression was significantly higher in squamous lung cancer than in adenocarcinoma, and the highly malignant ones were significantly higher than the low malignant ones.