Emerging drug resistance thwarts progress in chemotherapy, resulting in increased morbidity, mortality and healthcare costs. Understanding the mechanisms by which drug resistance phenotypes emerge is important to prolong the useful life of existing drugs but may also highlight pathways that play a role in the acquisition of resistance and which may themselves present resistance-proof drug targets. Comparative proteomic approaches have demonstrated potential to link drug resistance phenotypes to molecular changes but will also prove powerful in the elucidation of the mechanisms by which drug resistance arises.