The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self-renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients.