Vascular endothelial growth factor A (VEGF) is the most potent vascular growth signal controlling a wide spectrum of endothelial cell behaviours, including proliferation, migration, differentiation and survival. The versatility of VEGF signalling is reflected in the complex composition of its cell surface receptors and their ability to activate a variety of different downstream signalling molecules. A major challenge for VEGF research is to determine which of the specific signalling pathways control development of embryonic vasculature. PI3K is well known to mediate many effects downstream of VEGF signalling, in particular angiogenic sprouting and vascular remodelling. Conversely, the phosphatase PTEN that reduces cellular levels of PIP3 is also known to play an essential role in angiogenesis. Here we present data detailing the essential role of another mammalian specific phosphatase in the PI3K signalling pathway. Our results implicate the inositol polyphosphatase family as key mediators of endothelial cell migration in vivo and identiy an unexpected link to the Notch signalling pathway. These finding have significant implications to the current treatment regimes for anti angiogenic therapies.