Prognostication of newly diagnosed colorectal cancer (CRC) predominantly relies on stage as defined by the UICC-TNM and American Joint Committee on Cancer classifications. Tumour extent, lymph node status, tumour grade and the assessment of lymphatic and venous invasion are still the most important morphological prognostic factors. Evidence suggests that tumour budding and tumour border configuration are important, additional histological parameters but are not regarded as essential in prognosis. Although several molecular features, such as LOH18q and TP53 mutation analysis, have shown promising results in terms of their prognostic value, the American Society of Clinical Oncology Tumor Markers Expert Panel does not currently recommend their use in routine practice. cDNA-microarray, PCR and fluorescence in situ hybridisation are now frequently used to identity potential prognostic indicators in CRC, but the applicability of these methods in routine use is likely to have limited impact. Reliable prognostic markers identified by immunohistochemical protein profiling have yet to be established. Randomisation of data sets, assessment of interobserver variability for protein markers and scoring systems, as well as the use of receiver operating characteristic curve analysis in combination with multimarker-phenotype analysis of several different markers may be an effective tactical approach to increase the value of immunohistochemical findings. This article reviews the well established and additional prognostic factors in CRC and explores the contribution of molecular studies to the prognostication of patients with this disease. Additionally, an approach to improve the prognostic value of immunohistochemical protein markers is proposed.