The advent of next-generation sequencing (NGS) has revolutionized thoracic pathology, enabling comprehensive genomic profiling of non-small cell lung cancer (NSCLC) from limited diagnostic material. This review discusses NGS applications in predictive molecular pathology, emphasizing its role in identifying actionable mutations that guide targeted and immunotherapies in both early and advanced stages. The integration of NGS with liquid biopsy, immunohistochemistry, and optimized pre-analytical procedures enhances diagnostic precision and resistance-mechanism detection. Economic analyses demonstrate NGS as a cost-effective solution compared to single-gene testing, especially when multiple biomarkers are analyzed. Moreover, NGS supports differential diagnosis in thoracic neoplasms and cases with multiple pulmonary lesions by clarifying clonal relationships. The paper underscores the multidisciplinary approach required for implementing precision medicine and highlights the expanding clinical utility of NGS in diagnostic, prognostic, and therapeutic decision-making for thoracic tumors.