Mir-27b is a systems integrator of pro- and antiangiogenic signals at the posttranscriptional level via repression of Dll4 and Spry2 expression. Antiangiogenic stimuli result in down-regulation of miR-27b expression that allows for Spry2 and Dll4 expression, which blocks capillary branching and tip endothelial cell fate, respectively. Furthermore, miR-27b down-regulates Flt1 through Dll4/Notch signaling, further repressing vascular sprouting. Proangiogenic stimuli result in miR-27b expression, enabling posttranscriptional silencing of Dll4 and Spry2 and suppression of Flt1, which enhances tip cell numbers and promotes vascular sprouting. Such context-dependent bimodal action of mir-27b shapes appropriate angiogenesis response in health and disease.