Colorectal cancer progression is characterized by the sequential acquisition of multiple genetic aberrations. Insights into the biology of cancer cell and the development of novel methodologies have open a new frontier in the search of independent molecular factors to better predict outcome. Besides the generation of a large list of candidate markers, their applicability in routine clinical settings has been hindered by the heterogeneity of the disease. The analysis of cumulated genetic damage offers a more comprehensive measure of the cancer cell's genomic disruption and appears as a gauge of malignant potential. The prognostic application of different determinants of genomic damage is reviewed.