Tumour endothelium is a new target for anticancer treatments. Proliferating endothelial cells from the tumour, even if qualitatively different from those of blood vessels in the normal tissue of origin, remain putatively normal and genetically stable cells. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses (a tenth to a third of the maximum tolerated dose), known as ‘metronomic’ chemotherapy, increases the antiangiogenic activity of the drugs. The effects of these metronomic schedules of cytotoxic agents may be further enhanced by concurrent administration of novel, selective, treatments that inhibit, at a molecular level, the processes of tumour formation and growth eg angiogenesis, growth factor pathways, and other signal transduction cascades. The need to treat patients for long periods also supports the use of metronomic scheduling for chemotherapy, to minimise toxicity and to target both proliferating tumour cells and endothelial cells. This review describes the experimental studies involving metronomic schedules of chemotherapy, alone and in combination with angiogenesis inhibitors, and suggests a new therapeutic anticancer paradigm for controlling cancer by long-term therapy, based on the development of combinations of metronomic cytotoxic agents with individually tailored compounds designed to target specific molecules.