Non-small-cell lung cancers (NSCLCs) are the most common type of lung cancer, characterized by diverse pathological features. Recent advancements in genomic and signaling pathway analyses have revealed that NSCLCs are a group of distinct diseases with significant genetic and cellular heterogeneity. This heterogeneity has led to the identification of numerous potential therapeutic targets, significantly altering the clinical evaluation and treatment of patients. While many targeted therapies have shown promising clinical results, treatment responses are often short-lived. Further studies on the tumor microenvironment have opened new avenues for controlling NSCLC, including immunotherapy. NSCLCs are primarily classified based on histological characteristics, with adenocarcinoma (ADC) and squamous cell carcinoma (SCC) being the two predominant subtypes. ADCs arise in more distal airways and are associated with non-smokers, while SCCs are more common in proximal airways and are strongly linked to smoking and chronic inflammation. Recent genomic studies have identified a wide range of mutations and copy number alterations in NSCLCs, including *KRAS*, *BRAF*, *EGFR*, *HER2*, *MET*, *FGFR1*, *FGFR2*, *ALK*, *ROS1*, *NRG1*, *NTRK1*, and *RET*. These mutations have been validated through preclinical studies and are associated with sensitivity to clinical inhibitors. The tumor microenvironment, which includes extracellular matrix, mesenchymal cells, immune cells, and vasculature, plays a crucial role in tumor initiation and growth. Carcinoma cells interact with these components, and the microenvironment can either promote or prevent tumor progression. For example, tumor-associated macrophages (TAMs) and neutrophils can influence angiogenesis and matrix degradation, respectively. The PD1–PDL1 checkpoint, which involves the interaction between tumor cells and immune cells, has also been identified as a potential therapeutic target. The cells of origin for NSCLCs remain largely unknown, but studies using genetically engineered mouse models (GEMMs) have suggested that different cell types may give rise to distinct subtypes. For instance, club cells and alveolar epithelial type 2 (AT2) cells have been implicated in ADC, while basal cells are associated with SCC. Understanding the cells of origin and their interactions with the microenvironment is crucial for developing more effective treatments. Integrated therapies that target multiple cellular compartments, such as tumor vasculature, fibroblasts, and immune cells, are being explored. Additionally, epigenetic and metabolic targets, such as bromodomain inhibitors and metabolic enzymes, are showing promise in preclinical studies. The future of NSCLC treatment may involve genotype-dependent, carefully selected combinations of therapies to enhance tumor immune reactions, inhibit angiogenesis, and block interactions between tumor cells and stromal cells.Non-small-cell lung cancers (NSCLCs) are the most common type of lung cancer, characterized by diverse pathological features. Recent advancements in genomic and signaling pathway analyses have revealed that NSCLCs are a group of distinct diseases with significant genetic and cellular heterogeneity. This heterogeneity has led to the identification of numerous potential therapeutic targets, significantly altering the clinical evaluation and treatment of patients. While many targeted therapies have shown promising clinical results, treatment responses are often short-lived. Further studies on the tumor microenvironment have opened new avenues for controlling NSCLC, including immunotherapy. NSCLCs are primarily classified based on histological characteristics, with adenocarcinoma (ADC) and squamous cell carcinoma (SCC) being the two predominant subtypes. ADCs arise in more distal airways and are associated with non-smokers, while SCCs are more common in proximal airways and are strongly linked to smoking and chronic inflammation. Recent genomic studies have identified a wide range of mutations and copy number alterations in NSCLCs, including *KRAS*, *BRAF*, *EGFR*, *HER2*, *MET*, *FGFR1*, *FGFR2*, *ALK*, *ROS1*, *NRG1*, *NTRK1*, and *RET*. These mutations have been validated through preclinical studies and are associated with sensitivity to clinical inhibitors. The tumor microenvironment, which includes extracellular matrix, mesenchymal cells, immune cells, and vasculature, plays a crucial role in tumor initiation and growth. Carcinoma cells interact with these components, and the microenvironment can either promote or prevent tumor progression. For example, tumor-associated macrophages (TAMs) and neutrophils can influence angiogenesis and matrix degradation, respectively. The PD1–PDL1 checkpoint, which involves the interaction between tumor cells and immune cells, has also been identified as a potential therapeutic target. The cells of origin for NSCLCs remain largely unknown, but studies using genetically engineered mouse models (GEMMs) have suggested that different cell types may give rise to distinct subtypes. For instance, club cells and alveolar epithelial type 2 (AT2) cells have been implicated in ADC, while basal cells are associated with SCC. Understanding the cells of origin and their interactions with the microenvironment is crucial for developing more effective treatments. Integrated therapies that target multiple cellular compartments, such as tumor vasculature, fibroblasts, and immune cells, are being explored. Additionally, epigenetic and metabolic targets, such as bromodomain inhibitors and metabolic enzymes, are showing promise in preclinical studies. The future of NSCLC treatment may involve genotype-dependent, carefully selected combinations of therapies to enhance tumor immune reactions, inhibit angiogenesis, and block interactions between tumor cells and stromal cells.