The growth and development of most solid tumors require that they form their own functional vascular supply, which they do from the host normal vascular network by the process of angiogenesis. The significance of this neo-vasculature makes it an excellent target and two forms of vascular targeting agents (VTAs) have evolved; those that inhibit the angiogenesis process (angiogenesis inhibitors, AIs) and those that damage the already established vessels (vascular disrupting agents, VDAs). Although both AIs and VDAs can have substantial anti-tumor activity, neither induce tumor control, thus for their full clinical potential to be achieved they will need to be combined with more conventional cancer therapies. Numerous pre-clinical studies have demonstrated the efficacy of combining AIs and VDAs with radio- and chemo-therapy and many of these approaches are now under clinical evaluation. Although the tumor is the target for VTA therapy the normal host cells play an important role in VTA efficacy. Host cells such as infiltrating macrophages, neutrophils, mast cells, platelets, endothelial cells, and stromal fibroblasts can all produce the important growth factors that initiate angiogenesis. Many of these host cells also actively participate in the physical steps of angiogenesis including destabilization of existing vessels, blood vessel sprouting, endothelial cell migration and proliferation, and vessel stabilization. There is some evidence that these host cells can also influence VTA treatment, either by helping to normalize tumor vessels when AIs are administered or stimulate tumor angiogenesis after treatment with VDAs. The host itself also plays a critical role. Cancer patients undergoing therapy are normally treated to tolerance, thus the normal tissue side effects actually control the effective dose given to the tumor. All VTAs currently in clinical development induce some form of systemic side effects, which range from being rather mild and tolerable to more severe and even life threatening. For more localised therapies there is also the issue of possible VTA-enhanced local tissue reactions. A few pre-clinical studies have investigated this with radiation, but failed to show any enhancement of radiation-induced normal tissue damage by VTAs. Clearly, the therapeutic benefit of VTA treatment will depend on a balance between tumor and host related effects, and in this review we will consider the contribution of each.