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Colorectal cancer is the third most common malignancy in the United States. Improved detection sensitivity of early colorectal neoplasms would have important clinical applications. Herein, we report on using phage display to generate peptide libraries that detect colon carcinoma tissues. To accomplish this, we employed positive selection of a peptide-bearing phage library on poorly differentiated colon carcinoma cells (HT29) and combined this with negative selection of the phage library on well-differentiated colon carcinoma cells (HCT116). Analysis of the resulting library identified a nine-amino-acid, disulfide-constrained peptide, CPIEDRPMC (RPMreI), that stained HT29 colon carcinoma cells. Immunohistochemical staining using FITC-conjugated RPMreI peptide also showed binding of RPMreI to colon tumor tissues from four patients. We saw no binding of RPMreI to normal colon tissues. In addition, RPMreI failed to stain a panel of noncolon tissues including the lungs, liver, stomach. We further demonstrated that RPMreI coupled to the mitochondrial toxin (KLAKLAK)2 killed HT29 cells. These studies suggest that RPMreI may be a promising lead candidate in the development of a useful colon tumor diagnostic and targeted drug delivery agent.