It is generally accepted that angiogenesis plays a major role in tumor growth and numerous targeting agents directed against angiogenesis pathways have been developed and approved for clinical use. In the past years the concept of angiogenesis has developed into a multi-faceted process in which, besides local activation and division of endothelial cells, bone marrow derived progenitor cells (BMDPCs) contribute to neovascularization. A multitude of preclinical and clinical data indicates that the release of BMDPCs influences the response to certain anti-cancer modalities. In this review we provide an overview of all the preclinical and clinical studies contributing to this hypothesis and translate these findings to the clinic by pointing out the clinical implications these findings might have. The recent insight in the mechanism of a systemic host response, in response to various treatment modalities has shed new light on the mechanism of tumor regrowth, early recurrence and metastasis formation during or after treatment. This provides various new targets for therapy which can be used to improve conventional chemotherapy. Furthermore it provides a potential explanation why bevacizumab selectively enhances the effectiveness of only certain types of chemotherapy.