The concept that cancer might arise from a rare population of cells with stem cell-like properties was proposed 150 years ago. Increasing evidence during the past 2 decades suggests the existence of a small subgroup of cells in cancer that are responsible for tumor growth and proliferation. Stem cells have self-renewing properties; thus, they are appealing candidates for generating the malignant phenotype. Although the concept of stem cells in leukemia has received significant attention for more than the past decade, over the past several years, expression of several surface markers on cancer cells has led to identification of tumor-initiating cells in several solid tumors, including melanoma, brain, breast, prostate, liver, pancreatic, ovarian, and recently, colon cancer. This review will provide an update of the biologic basis of the stem cell model and possible targets for the treatment of colon cancer.