Among novel promising approaches that have recently entered the scene of anti-cancer therapy angiogenesis inhibition and targeting cancer-causing genes (e.g. oncogenes) are of particular interest as potentially highly synergistic. One reason for this is that transforming genetic lesions driving cancer progression (e.g. mutations of ras and/or p53) are thought to be causative for the onset of tumor angiogenesis and thereby responsible for build up of vascular supply which is essential for cancer cell survival, malignant growth, invasion and metastasis. However, many of the same genetic alterations that emerge during disease progression and repeated rounds of mutagenic and/or apoptosis causing therapy could alter cellular hypoxia-, growth factor- and apoptotic pathways in such a manner, as to also render cancer cells (partially) refractory to the detrimental consequences of poor blood vessel accessibility (density), ischemia, hypoxia and growth factor deprivation. As recent experimental evidence suggests, such cancer cells could therefore display a reduced vascular demand and remain viable even in poorly perfused regions of the tumor as well as possess an overall growth/survival advantage. The latter circumstance may lead to (predict) diminished efficacy of anti-angiogenic agents in certain malignancies. Therefore, we propose that analysis of oncogenic pathways and gene expression profiling of cancer cells may lead to important clues as to potential efficacy of anti-angiogenic therapies, the direct target of which is the host vasculature, but which are ultimately aimed at (indirect) destruction/control of the cancer cells population. We also suggest that oncogene (tumor suppressor)-directed therapies may help reverse diminished vascular demand of highly transformed cancer cells and thereby facilitate (sensitize tumors to) therapies directed against vascular supply of cancers and their metastases.