The main predictor of outcome of patients with colorectal cancer (CRC) remains the TNM staging system. Biomarkers, i.e. biological indicators of disease progression or of responsiveness to a pharmacological intervention, are expected to be of help in the management of CRC. Despite high expectations, biomarkers have not entered into clinical practice due to contradictory results of large-scale studies and to some complexity in data interpretation. Here we briefly review the main genetic and immunological changes that have been considered potential CRC biomarkers and that might be considered for further testing aimed at clinical use, at least in specific disease settings.