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Resistance is a constant presence in chemotherapy treatment. The very action of these therapeutic compounds causes resistance to these drugs. There are two modes of resistance to chemotherapy: the cancer cells themselves can undergo modifications that result in resistance, known as cell-intrinsic resistance. Alternatively, the non-malignant cells surrounding the tumor can undergo modifications that result in chemo-protection of the nearby malignant cells, known as cell-extrinsic resistance. Both of these modes of resistance have been extensively studied in the lab, however our knowledge is not advanced enough to subvert chemotherapy resistance in the clinic. To further our knowledge of chemotherapy resistance with the ultimate goal of reducing or eradicating this public health challenge, I have studied mechanisms of cell-intrinsic and cell-extrinsic resistance. I first studied how to best choose the drugs in a combination regimen to reduce the emergence of chemotherapy resistance.