Acquired resistance has curtailed cancer survival since the dawn of the chemotherapy age more than half a century ago. Although the application of stem cell (SC) concepts to cancer captured the imagination of scientists for many years, only the last decade has yielded substantial evidence that cancer SCs (CSCs) contribute to chemotherapy resistance. Recent studies suggest that the functional and molecular properties of CSCs constitute therapeutic opportunities to improve the efficacy of chemotherapy. Here we review how these properties have stimulated combination strategies that suppress acquired resistance across a spectrum of malignancies. The clinical implementation of these strategies promises to rejuvenate the effort against an enduring challenge.