Lung cancer is a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) comprising various molecular oncogenic subsets that significantly impact prognosis and management. Over the past two decades, significant progress has been made in identifying and targeting new molecular alterations, particularly in lung adenocarcinoma. Targetable molecular alterations are identified in approximately 60% of Western patients and 80% of Asian patients, often among non-smokers, East Asians, and younger individuals. Key druggable targets include EGFR, ALK, BRAF, ROS1, KRAS, HER2, MET, NTRK, RET, and NRG1. Next-generation sequencing (NGS) has revolutionized the identification of these alterations, offering high-throughput, speed, and depth in genomic analysis. Despite the availability of NGS, molecular testing is underutilized in many regions, and liquid biopsies, such as circulating tumor DNA (ctDNA), are being explored to overcome tissue sampling limitations. The article discusses the diagnostic approach to oncogenic drivers in advanced NSCLC, focusing on their pathophysiology, management, and future perspectives, while also addressing the challenges and shortcomings in this rapidly evolving field.Lung cancer is a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) comprising various molecular oncogenic subsets that significantly impact prognosis and management. Over the past two decades, significant progress has been made in identifying and targeting new molecular alterations, particularly in lung adenocarcinoma. Targetable molecular alterations are identified in approximately 60% of Western patients and 80% of Asian patients, often among non-smokers, East Asians, and younger individuals. Key druggable targets include EGFR, ALK, BRAF, ROS1, KRAS, HER2, MET, NTRK, RET, and NRG1. Next-generation sequencing (NGS) has revolutionized the identification of these alterations, offering high-throughput, speed, and depth in genomic analysis. Despite the availability of NGS, molecular testing is underutilized in many regions, and liquid biopsies, such as circulating tumor DNA (ctDNA), are being explored to overcome tissue sampling limitations. The article discusses the diagnostic approach to oncogenic drivers in advanced NSCLC, focusing on their pathophysiology, management, and future perspectives, while also addressing the challenges and shortcomings in this rapidly evolving field.