Neovascularization is one of the hallmarks associated with tumor growth. In the recent years, a number of angiogenesis inhibitors have been approved for clinical use in cancer patients. However, the efficacy of antiangiogenic therapy is in most cases short-lasting, with likely drug resistance developing within a few months. It is becoming clear also that there are a subset of malignant tumors that are inherently resistant to angiogenesis inhibition. The knowledge regarding resistance mechanisms towards angiogenesis inhibitors is still evolving and here we propose some theories and in some cases provide experimental evidence.