The development and progression of colorectal cancer (CRC) is a process that accumulates the driver somatic mutations elicited by chronic inflammation. Epigenetic modifications and genetic mutations play key roles in the whole evolutionary process of chronic inflammation-induced CRC. Adenoma gradually progresses into adenocarcinoma via accumulating genetic mutations stimulated by cancer promoting stimulations. The next generation sequencing technology provides an effective way to identify the "driver" mutations and fusion genes in the carcinogenesis, providing molecular evidences for cancer evolution. The most significant genetic changes during malignant transformation from adenoma to adenocarcinoma are the significant increases in microsatellite instability and chromosome instability. The main purpose of investigating the evolutionary process of CRC, especially somatic mutations, is to identify the related signaling pathways, which are the key steps to explore early effective intervention strategies and targeted therapies for CRC.