Lymphangiogenesis is supported by two homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell secretion in vitro, and recent studies have implicated the protease ADAMTS3 and the secreted factor CCBE1 in this process. How ligand proteolysis is controlled at the molecular level and how it regulates lymphangiogenesis remain poorly understood because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. In the present study, we use new biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 is required to convert VEGFC but not VEGFD to an active ligand. Consistent with these ex vivo findings, mouse genetic studies demonstrate that ADAMTS3 is required for lymphatic development in a manner identical to VEGFC and CCBE1, and that CCBE1 is required for lymphangiogenesis stimulated by VEGFC but not VEGFD in vivo. These studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may stimulate lymphatic growth during inflammation or wound healing.