There has been a major improvement in our understanding in the area of the genetics of CRC in the last decade. Reason for this is partly that CRC has a strong hereditary trait and premalignant lesions are frequent and easily accessible. In the 1990-ies the mutations responsible for the adenoma-carcinoma sequence were discovered on after the other. In the second part of the review the authors discuss the genetic background of sporadic and IBD associated colorectal cancers as well as the role of genetics in the diagnosis, prognosis and prediction of therapy. Chromosomal instability (85%) and microsatellite instability with or without change in DNA methylation (15%) are the main mechanisms involved in the pathogenesis of sporadic colorectal cancers. It became evident that no ultimate mutations exist. Most of neoplasms are genetically heterogeneous, independent pathways and simultaneous tumorigenesis may exist within the same organ, also in the colon. Gene expression profile, clinical phenotype and prognosis may also vary according to the location. Similar genetic mutations may be found in IBD associated colorectal cancers, however, the typical sequence and importance of mutations is different. In future, fecal DNA testing may be an important screening tool for colorectal cancer; however, its routine use is still limited by its low sensitivity. Similarly, genetic investigation may play an increasing role in the prediction of prognosis, therapy and complication of chemotherapy. A more distant goal may be the individualization of the therapy.