Drug resistance is a major cause for the failure of both chemotherapies and targeted drugs. Among leukemias and lymphomas, intrinsic resistance, i.e., present from the outset of treatment, is much less common than in epithelial malignancies, but acquired resistance often manifests itself during the course of therapy or at relapse. In this chapter, we review reasons for the failure of systemic cancer therapies and attempts to reverse drug resistance, particularly multidrug resistance (MDR) related to expression of P-glycoprotein (P-gp).