In sprouting angiogenesis, endothelial cells must orientate in the tissue environment in order to effectively invade tissues and form vascular patterns according to the local needs. Here, we review recent data indicating that sprouting angiogenesis is a guided process resembling axonal guidance and insect trachea formation. Angiogenesis requires functional specialization of endothelial cells within the sprout. Cells situated at the tip of the sprouts sense and navigate the environment using long filopodia, whereas cells in the sprout stalks proliferate and form a vascular lumen. Migration of the tip cells depends on a graded distribution of VEGF-A and activation of VEGFR2 located on the tip-cell filopodia. Proliferation in the stalk is concomitantly regulated by the local VEGF-A levels. Thus, the shape of the VEGF-A gradient controls the balance between tip cell migration and stalk cell proliferation, which in turn determines the initial vascular pattern. An imbalance between the two processes may explain why abnormal vascular patterns develop in pathological angiogenesis.