Colorectal cancer (CRC) is one of the most frequent cancers in the Western world and represents a major health burden. CRC development is a multi-step process that spans 10-15years, thereby providing an opportunity for early detection and even prevention. As almost half of all patients undergoing surgery develop recurrent disease, surveillance is advocated, albeit with various means and intervals. Current screening and surveillance efforts have so far only had limited impact due to suboptimal compliance. Currently, CEA is the only biomarker in clinical use for CRC, but has suboptimal sensitivity and specificity. New and better biomarkers are therefore strongly needed. Non-invasive biomarkers may develop through the understanding of colorectal carcinogenesis. Three main pathways occur in CRC, including chromosomal instability (CIN), microsatellite instability (MSI) and epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological, and genetic characteristics, which can be used for molecular classification and comprehensive tumour profiling for improved diagnostics, prognosis and treatment in CRC. Molecular-biological research has advanced with the sequencing of the human genome and the availability of genomic and proteomic high-throughput technologies using different chip platforms, such as tissue microarrays, DNA microarrays, and mass spectrometry. This review aims to give an overview of the evolving biomarker concepts in CRC, with concerns on methods, and potential for clinical implications for the surgical oncologist.