The ability of cancer cells to experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally unrelated chemotherapeutic agents, termed multidrug resistance (MDR), is the most common cause of chemotherapy failure. Research has firmly established that most tumors developing MDR are often associated with the over-expression of permeability-glycoprotein (P-gp), the most extensively characterized of the drug efflux pumps. The development of P-gp inhibitors is acknowledged as a viable means of reversing this MDR phenotype and has received considerable attention throughout the past two decades. However, most P-gp inhibitors identified to date have demonstrated limited clinical success due to limitations in potency and specificity. This paper reviews the most recent discoveries relating to the medicinal chemistry of P-gp inhibitors that are presently in development. In light of this information, this paper seeks to suggest new treatment options for the MDR phenotype.