Non-small-cell lung cancers (NSCLCs) are a heterogeneous group of diseases with diverse genetic and cellular characteristics. Recent genomic studies have revealed a wide range of mutations and genetic alterations in NSCLCs, leading to the identification of potential therapeutic targets. These findings have transformed the clinical evaluation and treatment of NSCLC patients. However, treatment responses are often short-lived, prompting the exploration of new therapeutic strategies, including immunotherapy. NSCLC is the most common type of lung cancer, accounting for over 85% of cases, with a 5-year survival rate of 15.9%. Advances in next-generation sequencing (NGS), genetically engineered mouse models (GEMMs), and large tumor databases have provided a deeper understanding of NSCLC at the molecular and genetic level. These studies have identified key mutations in genes such as EGFR, KRAS, BRAF, HER2, MET, FGFR1, FGFR2, FGFR3, ALK, ROS1, and RET, which are associated with different subtypes of NSCLC. These mutations are often targeted by specific inhibitors, leading to improved treatment outcomes. The tumor microenvironment plays a crucial role in NSCLC progression, with immune cells, fibroblasts, and the extracellular matrix contributing to tumor growth and survival. The PD1-PDL1 checkpoint has been targeted in clinical trials, showing promising results in some cancer subtypes, including NSCLC. However, the effectiveness of these treatments varies among patients, highlighting the need for personalized approaches. The origin of NSCLC cells is still not fully understood, but studies suggest that different cell types may give rise to distinct NSCLC subtypes. For example, club cells, alveolar type II cells, and bronchiolar stem cells have been implicated in the development of different NSCLC subtypes. These findings underscore the importance of understanding the cellular origins of NSCLC to develop more effective treatments. Tumor-propagating cells (TPCs) are a subset of cancer cells with stem-like properties that can initiate and sustain tumor growth. These cells are resistant to conventional therapies and may contribute to tumor recurrence and metastasis. Targeting TPCs is a promising approach for improving treatment outcomes in NSCLC. Current treatments for NSCLC include targeted therapies for specific mutations, such as EGFR, ALK, and ROS1, as well as immunotherapy targeting the PD1-PDL1 checkpoint. However, resistance to these treatments is common, necessitating the development of combination therapies and new approaches to target multiple aspects of the tumor microenvironment. The integration of genomic, epigenomic, and proteomic data is essential for understanding the complexity of NSCLC and developing more effective treatments. Future research should focus on identifying the best combination of therapies that target different aspects of the tumor, including the tumor microenvironment, to improve patient outcomes.Non-small-cell lung cancers (NSCLCs) are a heterogeneous group of diseases with diverse genetic and cellular characteristics. Recent genomic studies have revealed a wide range of mutations and genetic alterations in NSCLCs, leading to the identification of potential therapeutic targets. These findings have transformed the clinical evaluation and treatment of NSCLC patients. However, treatment responses are often short-lived, prompting the exploration of new therapeutic strategies, including immunotherapy. NSCLC is the most common type of lung cancer, accounting for over 85% of cases, with a 5-year survival rate of 15.9%. Advances in next-generation sequencing (NGS), genetically engineered mouse models (GEMMs), and large tumor databases have provided a deeper understanding of NSCLC at the molecular and genetic level. These studies have identified key mutations in genes such as EGFR, KRAS, BRAF, HER2, MET, FGFR1, FGFR2, FGFR3, ALK, ROS1, and RET, which are associated with different subtypes of NSCLC. These mutations are often targeted by specific inhibitors, leading to improved treatment outcomes. The tumor microenvironment plays a crucial role in NSCLC progression, with immune cells, fibroblasts, and the extracellular matrix contributing to tumor growth and survival. The PD1-PDL1 checkpoint has been targeted in clinical trials, showing promising results in some cancer subtypes, including NSCLC. However, the effectiveness of these treatments varies among patients, highlighting the need for personalized approaches. The origin of NSCLC cells is still not fully understood, but studies suggest that different cell types may give rise to distinct NSCLC subtypes. For example, club cells, alveolar type II cells, and bronchiolar stem cells have been implicated in the development of different NSCLC subtypes. These findings underscore the importance of understanding the cellular origins of NSCLC to develop more effective treatments. Tumor-propagating cells (TPCs) are a subset of cancer cells with stem-like properties that can initiate and sustain tumor growth. These cells are resistant to conventional therapies and may contribute to tumor recurrence and metastasis. Targeting TPCs is a promising approach for improving treatment outcomes in NSCLC. Current treatments for NSCLC include targeted therapies for specific mutations, such as EGFR, ALK, and ROS1, as well as immunotherapy targeting the PD1-PDL1 checkpoint. However, resistance to these treatments is common, necessitating the development of combination therapies and new approaches to target multiple aspects of the tumor microenvironment. The integration of genomic, epigenomic, and proteomic data is essential for understanding the complexity of NSCLC and developing more effective treatments. Future research should focus on identifying the best combination of therapies that target different aspects of the tumor, including the tumor microenvironment, to improve patient outcomes.