Metastasis-associated genomic alterations have been recognized to play a critical role in tumor metastasis. Primary and metastatic tumor cells in mice and tumors in a patient were studied by cDNA array analysis. Selected genes were determined by RT-PCR and immunohistochemistry. Pathways on changed genes were statistically analyzed. The function of Grb2 was determined by in vitro wound assay. Nodal metastatic cells had a stronger ability of growth and metastasis than primary tumor cells. A total of 376 genes showed a different expression between primary and metastatic cells. The expression of Grb2 and genes in the Grb2-mediated pathways was significantly elevated in the metastases. Elevated levels of Grb2 expression in metastases were related to the distant metastasis of colorectal carcinoma. Blocking the Grb2-SH2 domain signaling transduction inhibited cell motility. Metastasis-associated genes identified by cDNA and tissue microarrays provide potentially valuable information on the metastasis of colorectal tumors. Overexpression of Grb2 may contribute to tumor growth, invasiveness and metastasis.