This review examines critically recent advances published in 2004 and selected articles of interest published in early 2005 that explore the interface between molecular technology and classical staging of colorectal cancer. Although conventional staging remains the gold standard for deriving clinically important prognostic groups, additional markers may be of independent prognostic value with respect to survival and have predictive value with respect to response to adjuvant therapy. This review focuses on TP53, K-ras, DCC, DNA microsatellite instability, CD8-positive intraepithelial lymphocytes, thymidylate synthase, and gene expression profiling as prognostic and predictive markers. It also considers the role of immunohistochemistry, reverse transcriptase polymerase chain reaction, and sentinel lymph node sampling as adjuncts to staging lymph node spread.