Metastasis is responsible for most cancer deaths. Recently, we have found that Notch signaling stimulates colon cancer metastasis. In tumor cells, Notch signaling is triggered by ligands on adjoining blood vessels, and stimulates transendothelial migration. We have also found that Aes (or Grg5) inhibits the Notch signaling pathway in colon cancer cells, resulting in metastasis suppression. Genetic depletion of Aes in ApcΔ716 intestinal polyposis mice has caused marked tumor invasion and intravasation. Consistently, the malignant phenotypes have been suppressed by treatment with a gamma-secretase inhibitor or additional knockout of Rbpj. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis. As a model for colon cancer invasion and intravasation, compound mutant mice for the Apc and Aes genes should be useful to evaluate upcoming therapeutics including Notch signaling inhibitors against colon cancer metastasis.