Polyploidisation (increase in DNA copy number in a cell) is a mechanism that allows the generation of very large cells and can be achieved through a number of routes. In addition to cell fusion, cells can undergo endocycle (DNA replication without mitosis) or endomitosis (one type being mitosis in the absence of cytokinesis). In Drosophila, the subperineural glia (SPG) of the larval brain, which form the blood-brain barrier (BBB), are polyploid but, unlike in most other fly tissues, both mononucleate and multinucleate cells can be found. Now, Terry Orr-Weaver and colleagues investigate how polyploidy is achieved and regulated in these cells. They find that SPG initially endocycle, but then many undergo endomitosis, such that at late stages most cells are multinucleate with most of their nuclei polyploid. Hence, there appears to be a developmental transition in cell cycle mode. How might this switch be controlled? The authors show that String, a crucial activator of mitosis, is required for endomitosis in this system, while Notch signalling inhibits endomitosis and maintains endocycles. Inhibiting or promoting endomitosis, through inhibition of String or Notch signalling, respectively, disrupts BBB function, demonstrating that tight regulation of cell cycle mode is essential for maintaining barrier integrity and, more broadly, that control of polyploidy has profound consequences on cell size and function through development.