Resistance to chemotherapy is one of the major impediments to treatment success. Furthermore, experimental evidence suggests that drug resistance is a complex biological phenomena, with many influences that interact nonlinearly. In this talk, we present work on models of tumor heterogeneity and their impact on drug resistance. Specifically, we present a structured population model as a general framework for studying drug resistance, as well specific models of cell-cycle dynamics and its effect on cancer growth and treatment efficacy.