Many recent advances in cancer therapy have been based on an understanding of the basic biology of the cancer cell itself, particularly with respect to abnormalities in various signalling pathways. It has become increasingly apparent that malignant cells exist in a complex cellular and extracellular microenvironment, which can play key roles in the initiation and maintenance of the malignant phenotype. These interactions can provide therapeutic targets that are now being exploited in the clinic. Much attention has been paid to agents that disrupt angiogenesis or existing tumor vasculature, however other cellular and non-cellular components of the tumor mass mediate critical functions and can also be useful treatment targets. Treatments directed at these interactions bring new challenges in terms of how best to develop these strategies, and require approaches that differ in many ways from conventional anticancer therapies.