To date there is no genetic marker that gives accurate information on the prognostic impact for patients with colorectal cancer. A particular clone, not detected in the tumor, could be responsible for the metastatic process. To overcome this problem, genetic alterations were analyzed in metastatic tissues from 58 patients who developed metastases after curative surgery for colorectal cancer. K-ras, p53 and Smad4 alterations were observed in respectively 38, 60 and 27% of the metastases. These frequencies are similar to the ones reported in primary colorectal tumors. Thus, these genetic alterations cannot be used as prognostic biomarkers in patients with colorectal cancer. The metastases were stratified into 3 groups, according to the metastatic localization. K-ras mutations were detected in respectively 75, 26 and 11% of the distant, peritoneal and liver metastases. Loss of Smad4 expression was observed more frequently in the liver (62%) than in other metastases (13%). These results suggest that the genetic changes of the tumor cells indicate the location of the metastases and thus, the route of metastatic spread.