Significant advances have been made in understanding the biology of colorectal cancer. In this chapter, we review the key signaling pathways that play key roles in maintaining the growth and proliferation of colorectal cancer. The pathways that will be discussed include Wnt/beta-catenin, TGF-beta/SMAD, Notch, Hedgehog, epidermal growth factor receptor, Ras, and PI3K/Akt. In addition, we review the growing role of colon cancer stem cells in mediating cellular drug resistance and cancer recurrence. This enhanced understanding of cancer biology provides important insights for developing novel therapies that target specific growth factor receptors and/or certain critical signal transduction pathways. These targeted therapies can then be used alone or in combination with standard cytotoxic chemotherapy regimens.