Stefan Schulte-Merker and colleagues report that ccbe1, a predicted secreted protein, is required for embryonic lymphangiogenesis in zebrafish. Ccbe1 acts at the same stage as Vegfc, and is required for lymphangioblast budding and angiogenic sprouting from the venous endothelium. Lymphatic vessels have important roles in fluid homeostasis, fat absorption, inflammation and cancer metastasis and develop in a dynamic process (called lymphangiogenesis) involving budding, migration and proliferation of lymphangioblasts. Using a genetic screen in zebrafish we identify ccbe1 (collagen and calcium-binding EGF domain-1) as indispensible for embryonic lymphangiogenesis. Ccbe1 acts at the same stage of development as Vegfc and is required for lymphangioblast budding and angiogenic sprouting from venous endothelium.