The introduction of high-throughput sequencing with Next-Generation Sequencing (NGS) marked a significant advancement in the field. Over the past decade, NGS has helped to uncover molecular alterations that drive malignant behavior and provide crucial information for clinicians, directly influencing treatment options and significantly improving patient outcomes. This book focuses on the molecular alterations and signaling pathways identifiable through NGS and on the practical challenges encountered in daily diagnostic work. These include the management of scant or degraded material, the need to correlate molecular findings with morphology and ancillary techniques, and the limited availability of advanced sequencing platforms in many routine settings. Particular attention is given to tumor types in which NGS is still evolving or not yet fully standardized, allowing readers to appreciate both the opportunities and the limitations of the method. Each chapter is structured either around the molecular alteration’s characteristic of specific tumors or around broader theoretical concepts, with emphasis on decision-making algorithms and the resolution of common diagnostic problems. Next-Generation Sequencing in Solid Tumor Histopathology is designed not only for molecular pathology specialists but also for general surgical pathologists, who are increasingly required to interpret NGS reports and integrate them into daily diagnostic responsibilities, even in institutions without dedicated molecular facilities. The concluding sections address rapidly emerging technologies such as liquid biopsy, single-cell and spatial transcriptomics, and epigenomic and proteogenomic profiling, which are expected to enter routine practice in the near future and with which pathologists must become conversant.