Lung cancer classification and treatment has been revolutionized by improving our understanding of driver mutations and the introduction of tumor microenvironment (TME)-associated immune checkpoint inhibitors. Despite the significant improvement of lung cancer patient survival in response to either oncogene-targeted therapy or anticancer immunotherapy, many patients show initial or acquired resistance to these new therapies. Recent advances in genome sequencing reveal that specific driver mutations favor the development of an immunosuppressive TME phenotype, which may result in unfavorable outcomes in lung cancer patients receiving immunotherapies. Clinical studies with follow-up after immunotherapy, assessing oncogenic driver mutations and the TME immune profile, not only reveal the underlying potential molecular mechanisms in the resistant lung cancer patients but also hold the key to better treatment choices and the future of personalized medicine. In this review, we discuss the crosstalk between cancer cell genomic features and the TME to reveal the impact of genetic alterations on the TME phenotype. We also provide insights into the regulatory role of cellular TME components in defining the genetic landscape of cancer cells during tumor development.