One major burden in the development of first-generation anti-angiogenic therapy was to disregard several initially already evident facts: (i) subcutaneous murine tumor models are very different to polytopic metastasized human cancers (ii) vessel co-option is insufficiently targetable with VEGF inhibition (iii) though VEGF is a very potent proangiogenic factor many other cytokines can drive angiogenesis instead (iv) the complex microenvironment(s) of polytopic metastasized cancer diseases exploits a plethora of mechanisms to foster tumor progression independent of VEGF. The gene discussed is VEGFA; the disease is cancer.