Immune checkpoint blockade with PD-(L)1 antibodies has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Similarly, the identification and targeting of oncogene drivers in metastatic NSCLC has dramatically improved patient outcomes with an expanding list of potentially actionable alterations and targeted therapies. Many of these molecular aberrations are more common in patients with little or no smoking history and adenocarcinoma histology. Certain molecular subsets of NSCLC, though gaining greatly from targeted therapy approaches, may derive less benefit from immune checkpoint blockade. The optimal identification, targeting, and sequencing of targeted therapies, immunotherapy, and chemotherapy are essential to continue to improve patient outcomes in advanced NSCLC. Herein, we review the role of immunotherapy in locally advanced and metastatic disease for patients with actionable driver alterations. Never-smoking patients have a high probability of having lung cancer that harbors one of these molecular aberrations that can be matched to a tyrosine kinase inhibitor with greatly improved clinical outcomes. Some of these patients with driver mutations may derive less benefit from immune checkpoint inhibitor approaches (either alone or combined with chemotherapy), especially compared with smoking-associated NSCLC. Given that PD-1 blockade alone or with platinum-based chemotherapy is the de facto first-line therapy (depending on level of PD-L1 expression) for nontargetable metastatic NSCLC, we also review treatment in never-smoking patients for whom molecular testing results are pending and the likelihood of identifying a driver mutation is high.