Cancer remains a major cause of death from disease in both children and adults in developed countries. Drug resistance is a major factor in cancer treatment failure and effective therapies are required. The microtubule cytoskeleton is frequently disrupted in cancer and we have shown that this system mediates drug resistance, tumourigenesis and metastasis. Our recent studies have revealed key roles for specific microtubule proteins in metabolism and cell survival signalling pathways. Challenges remain in targeting specific microtubule proteins with small molecule agents due to the high degree of structural homology between family members. We have been developing nanoparticles (engineered materials at the nano meter scale) to encapsulate and deliver siRNA/miRNA and/or chemotherapeutic drugs to overcome resistance and reduce the toxic side effects of conventional chemotherapy. Systemic delivery of siRNA-loaded nanoparticles targeting microtubule proteins have led to effective gene silencing and a reduction in tumour growth against aggressive epithelial tumours in vivo. These findings open up opportunities to further refine the development of nanoparticles for delivery of “undruggable” cancer genes and chemotherapy.