Resistance mechanisms to chemotherapy in multiple myeloma include (1) reduced drug concentrations at the target site of action, (2) alterations in the drug target, and (3) inhibition or prevention of drug-induced apoptosis. Recent advances in understanding resistance mechanisms have resulted in the investigation of novel therapies for the treatment of patients with multiple myeloma. P-glycoprotein is a drug transport protein that decreases intracellular drug concentrations at the target site. Valspodar, a third-generation cyclosporine analog, is an inhibitor of P-glycoprotein that currently is being evaluated to potentially overcome this mechanism of drug resistance. P-glycoprotein inhibitors (also known as chemosensitizers) are being investigated for use in combination with chemotherapeutic agents to enhance the apoptotic effect and prevent resistance at the target site. Other novel approaches involve blocking pathways that result in the expression of antiapoptosis factors. Interleukin-6 is an important growth factor in myeloma and has been implicated in drug resistance via an antiapoptosis effect. In vitro blocking of an interleukin-6-dependent pathway with either a JAK inhibitor (tyrphostin, AG490) or STAT3 dominant negative (STAT3-DN) reduced expression of Bcl-xL (an antiapoptosis protein), increased spontaneous apoptosis, and enhanced sensitivity to Fas-mediated apoptosis. In conclusion, several cellular mechanisms reduce the response to drug therapy in multiple myeloma. Future treatment approaches for this condition most likely will involve combinations of agents to enhance response or prevent resistance.