Selective small-molecule kinase inhibitors have emerged over the past decade as an important class of anti-cancer agents, and have demonstrated impressive clinical efficacy in several different diseases, including relatively common malignancies such as breast and lung cancer. However, clinical benefit is typically limited to a fraction of treated patients. Genomic features of individual tumours contribute significantly to such clinical responses, and these seem to vary tremendously across patients. Additional factors, including pharmacogenomics, the tumour microenvironment and rapidly acquired drug resistance, also contribute to the clinical sensitivity of various cancers, and should be considered and applied in the development and use of new kinase inhibitors.