The lymphatic vasculature is a crucial component of the cardiovascular system, serving vital roles in tissue fluid homeostasis, immune cell trafficking and absorption of lipids from the digestive tract. Although signalling events important for development of the blood vasculature have been thoroughly investigated, less is known about the signalling pathways important for development of the lymphatic vasculature. Our work has revealed that the ubiquitin ligase Nedd4 is crucial for morphogenesis of the lymphatic vasculature during mouse embryogenesis; Nedd4-/- embryos exhibiting strikingly mis-patterned lymphatic vessels. Conditional deletion of Nedd4 selectively in lymphatic endothelial cells also results in aberrant lymphatic vessel patterning, demonstrating a cell autonomous requirement for Nedd4 during lymphatic vascular development. Here we demonstrate that Nedd4 regulates lymphangiogenesis via dual mechanisms. Firstly, Nedd4 orchestrates VEGFR3 trafficking following VEGF-C binding such that in the absence of Nedd4, VEGFR3 degradation is elevated, culminating in reduced activity of this key pro-lymphangiogenic signalling pathway. Secondly, Nedd4 regulates the remodelling of lymphatic endothelial cell junctions; in Nedd4 deficient LEC, intercellular junctions remain tightly associated due to elevated junctional levels of VE-Cadherin and β-catenin, thus restricting the capacity of cells to sprout and migrate. These combined effects of Nedd4 loss-of-function profoundly impact the ability of Nedd4 deficient endothelial cells to respond to growth stimuli important for developmental lymphangiogenesis.