Like all human cancers, colorectal cancer is a complicated disease. While a mature body of research involving colorectal cancer has implicated the putative sequence of genetic alterations that trigger the disease and sustain its progression, there is a surprising paucity of well-validated, clinically useful diagnostic markers of this disease. For prognosis or guiding therapy, single gene-based markers of colorectal cancer often have limited specificity and sensitivity. Genome-wide analyses (microarrays) have been used to propose candidate patterns of gene expression that are prognostic of outcome or predict the tumor's response to a therapy regimen; however, these patterns frequently do not overlap, and this has raised questions concerning their use as biomarkers. The limitation of gene-expression approaches to marker discovery occurs because the change in mRNA expression across tumors is highly variable and, alone, accounts for a limited variability of the phenotype, such as with cancer. More robust and accurate markers of cancer will result from integrating all the information we have about the cell: genomics, proteomics and interactomics. This article will discuss traditional markers in colorectal cancer, both genomic and proteomic, including their respective approaches and limitations, then conclude with examples of systems biology-based approaches for candidate marker discovery, and discuss how this approach is reshaping our view of a biomarker.