The advent of next-generation sequencing (NGS) has led to a paradigm shift in the management of solid neoplasms, and gastrointestinal neoplasms are a noteworthy example of this transformation. It is now possible to evaluate multiple genes with turnaround times that meet clinical needs and at a limited cost. Furthermore, technological advancements have led to the development of ever more complete panels, allowing for the analysis of hundreds of genes and intricate molecular signatures, such as homologous recombination or mismatch repair. While such panels enable the collection of a significant amount of molecular information, their real benefit remains uncertain, particularly in light of the increased cost and turnaround times and considering the requirement for more complex analysis and analytical platforms. Concurrently, technological advancements in NGS-based technologies have given rise to novel platforms that are able to analyze previously unexplored templates (e.g., RNA), thereby introducing novel potential biomarkers (e.g. transcripts, splice variants, methylation profiles, and other epigenetic modifications) with an extraordinary resolution that reaches the single-cell level.