With the rapid advancements in second-generation gene sequencing technologies, a growing number of driver genes and associated therapeutic targets have been unveiled for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). While they are clinically classified as non-small cell lung cancer (NSCLC), they display distinct genomic features and substantial variations in clinical efficacy, underscoring the need for particular attention. Hence, this review provides a comprehensive overview of the latest advancements in driver genes, epigenetic targets, chemotherapy, targeted therapy, and immunotherapy for LUAD and LUSC. Additionally, it delves into the distinctions in signaling pathways and pivotal facets of clinical management specific to these two categories of lung cancer. Moreover, we furnish pertinent details regarding clinical trials pertaining to driver genes and epigenetics, thus establishing a theoretical foundation for the realization of precision treatments for LUAD and LUSC.