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Lung cancer remains the leading cause of cancer death worldwide. Advances in genomic medicine have depicted biomarkers that stratify lung cancer based on driver mutations, and there are, a portion of the lung cancer that does not bear driver mutations. The successful development of targeted therapy represents a major breakthrough for the former, and the implement of immune checkpoint inhibitors is undoubtedly a paradigm shift for the latter. Nevertheless, despite those exciting breakthroughs within the past 20 years, quite a few barriers for lung cancer therapy awaits solutions. This talk will be addressing lung cancer therapeutic barriers, encompassing targeting barriers on CNS drug delivery, EGFR resistance, and immune checkpoint inhibitor clinical trial data interpretation.