Branching morphogenesis is a complex developmental process that has been studied thoroughly in the kidney, lung and mammary gland. But Pei-Hsin Huang and colleagues have been investigating branching morphogenesis in the mouse submandibular gland (SMG) - the salivary gland under the floor of the mouth -and on p. 2935,report the role of semaphorin signalling during the first step of SMG branching morphogenesis: the process of cleft formation. Semaphorin, together with its receptors neuropilin (Npn) and plexin (Plxn), is well known for its role in the nervous system and is involved in branching morphogenesis in other tissues. By downregulating or overexpressing combinations of these molecules in ex vivo SMG culture, the researchers show that the semaphorins Sema3A and Sema3C, the neuropilin Npn1 and the plexins PlxnA2 and PlxnD1, are specifically required for cleft formation. But the researchers were surprised to find that Sema3A and Sema3C function additively, with Npn1 mediating signals from both semaphorins, which contrasts with their antagonistic interactions in the lung and nervous system. The authors conclude that while semaphorin signalling has roles in branching morphogenesis in different tissues, it functions very differently in different contexts.