Cancer stem cells (CSCs) are a subpopulation of cells within tumors that possess the stem cell characteristics of self-renewal, quiescence, differentiation, and the ability to recapitulate the parental tumor when transplanted into a host. CSCs are correlated with poor clinical outcome due to their contribution to chemotherapy resistance and metastasis. Multiple cell surface and enzymatic markers have been characterized to identify CSCs within a heterogeneous tumor, and here we summarize ongoing preclinical and clinical efforts to therapeutically target these cells and improve patient outcomes. Stem Cells Translational Medicine  2019;8:75–81