Multidrug resistance in cancer poses a significant barrier to effective therapy and is often mediated by overexpression of the efflux transporter P-glycoprotein (P-gp). When expressed at normal levels at barrier sites throughout the body, this 170 kDa transmembrane pump confers a protective effect by transporting xenobiotics out of healthy cells. However, its affinity for structurally diverse lipophilic substrates, including many chemotherapeutics, renders it a challenging clinical target when overexpressed by cancer cells. P-gp overexpression has been reported in many different types of cancers and is associated with poor response to therapy and reduced survival rates. While early research efforts emphasized competitive inhibition as a primary means to circumvent P-gp, clinical trials have yielded minimal success, prompting ongoing work to develop effective strategies to resensitize cancer cells to treatment (Chapter 1). Though many sophisticated therapeutic platforms have been developed to circumvent P-gp, significant challenges remain. Small molecule inhibitors continue to be plagued by systemic toxicity, modest potency, and low site-specific accumulation. While recent years have seen a shift towards modulation of P-gp expression as an alternative to competitive inhibition, the quantitative relationship between P-gp receptor density and drug sensitivity remains undefined, rendering these studies difficult to contextualize. This work leverages engineering and drug delivery principles to address three significant challenges to successful circumvention of P-gp. In Chapter 2, novel copolymers of acrylic acid and quinidine, a P-gp inhibitor, are synthesized and evaluated for their ability to drive active targeting to drug resistant tumors in vivo. Chapter 3 explores symmetric homodimerization of aromatic pharmacophores as a strategy to modularly assemble potent P-gp inhibitors. Chapter 4 quantifies the relationship between P-gp receptor density and drug sensitivity in two distinct cell lines to enable prediction of cellular response to therapeutics following changes in P-gp expression. Taken together, these results present three distinct approaches to interrogate and modulate the function of P-glycoprotein and can inform future work to optimize therapeutic strategies for overcoming multidrug resistance in cancer.