There has been no significant improvement in the treatment of metastatic colon cancer over the last four decades. A major reason for therapeutic failure is the nonselective nature of conventional chemotherapy. Therefore, new selective therapeutic approaches must be explored to improve survival. Recent advances in cell and molecular biology have opened up new avenues of developing selective molecular therapy for colon cancer. In view of the heterogeneity of cells in colon cancer, it is likely that the use of more than one cellular target will be required to achieve a significant antitumor response. Mechanistic studies of how proliferation, differentiation and malignant properties are controlled by negative growth factors, positive growth factors and adhesion molecules have allowed the identification of several molecular targets of attack in colon cancer. Disruption of one or more of these targets should have a highly antiproliferative and/or cytotoxic effect on colon cancer cells. Additionally, disrupting the expression of these targets may augment sensitivity to conventional chemotherapy. In this article, we will discuss how polypeptide growth factors act in colon cancer cells, identify several molecular targets of attack and discuss strategies for selective disruption of these targets in colon cancer. Where appropriate, the biologic similarities or differences by comparison with other types of tumor will also be discussed.