Blood vessel networks expand to meet oxygen demands via sprouting angiogenesis. This process is heterogeneous but not random; as sprouts form and extend, neighboring endothelial cells do not sprout but divide. Sprouting is regulated by local sprout guidance cues produced by the vessels themselves, as well as extrinsic cues. Endothelial cells in developing vessels orient in several axes to establish migratory polarity, apical-basolateral polarity, and planar cell polarity. Although little is known about how polarity axes are set up or maintained, they are important for vessel formation and function. This review focuses on the current knowledge of how blood vessel sprouting is regulated and guided, the role of endothelial cell polarity in forming vessels, and how these processes affect vessel function and are potentially perturbed in pathologies with vascular components.