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Treatment resistance, whether inherent or acquired, is a major problem reducing the activity of conventional and newer, molecularly targeted, cancer drugs. A more complex picture of the causes and contributions of specific forms of resistance is now emerging through application of pharmacological, proteomic and gene expression technologies and we have entered an exciting time where new molecular research tools are being applied not only to characterise the causes of such resistance, but to identify rational new treatments and treatment combinations that are being rapidly translated to clinical evaluations with increasing success. This review outlines many of the contributing causes of resistance to established cytotoxics and to the new breed of molecularly targeted agents, both monoclonal antibodies and small molecules, and the research methods being used to wage war on resistant cancer.