Thousands or millions of sequences concurrently produced in next-generation sequencing process. Next-generation sequencing has become a commodity. Journal of Next Generation Sequencing & Applications, Advancements in Genetic Engineering, Journal of Computer Science & Systems Biology, Journal of Proteomics & Bioinformatics, Transcriptomics: Open Access, American Journal of Respiratory and Critical Care Medicine, Journal of Clinical Endocrinology and Metabolism, Journal of National Cancer Institute, EMBO Journal.Cancer research began to use this innovative and highly performing method, and interesting results started to appear in colorectal cancer (CRC) analysis. Several studies produced high-quality data in terms of mutation discovery, especially about actionable or less frequently mutated genes, epigenetics, transcriptomics. Analysis of results is unveiling relevant perspectives aiding to evaluate the response to therapies. Novel evidences have been presented also in other directions such as gut microbiota or CRC circulating tumor cells. However, despite its unquestioned potential, NGS poses some issues calling for additional studies. This review intends to offer a view of the state of the art of NGS applications to CRC through examination of the most important technologies and discussion of recent published results.