Organs like the vertebrate vascular system and the insect tracheal system develop from separate primordia that undergo fusion events to form interconnected tubular networks. Although the correct pattern of tubular connections (anastomoses) in these organs is crucial for their normal function, the cellular and molecular mechanisms that govern tube fusion are only beginning to be understood. The process of tube fusion involves tip cell specification, cell–cell recognition and contact formation, self-avoidance, changes in cell shape and topology, lumen formation, and luminal membrane fusion. Significant insights into the underlying cellular machinery have been gained from genetic studies of tracheal tube fusion in Drosophila. Here, we summarize these findings and we highlight similarities and differences between tube fusion processes in the Drosophila tracheae and in the vertebrate vascular system. We integrate the findings from studies in vivo with the important mechanistic insights that have been gained from the analysis of tubulogenesis in cultured cells to propose a mechanistic model of tube fusion, aspects of which are likely to apply to diverse organs and organisms.