Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression—leading to progression-free survival and overall survival benefits compared with standard therapy—in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting neoangiogenesis. Indeed, several studies have highlighted the possibility that inhibitors of VEGF (and its receptors) can promote an invasive metastatic switch, in part by creating an increasingly hypoxic tumour microenvironment. As a potential remedy, a number of therapeutic approaches have been investigated that target the hypoxic tumour compartment to improve the clinical outcome of antiangiogenic therapy.