The endocycle is a modified cell cycle consisting of solely S and G phases that is widely used in differentiated Drosophila tissues. DNA replication in the absence of mitosis and cell division increases ploidy and cell size. We find that in addition to the endocycle an alternate cell cycle, endomitosis, is utilized in the subperineurial glia (SPG) in the Drosophila brain. In this variant cycle, mitosis and nuclear division occur, but not cytokinesis. Thus cell number does not increase, and large multinucleate cells are produced. The SPG are the first identified endomitotic cells in Drosophila. The presence of both endocycling and endomitotic SPG raises the question of the function of each of the two cell cycle types. We previously showed that increased cell size of the SPG is crucial for their role in maintaining the blood-brain barrier as the neuronal mass of the nervous system increases during development. Therefore we analyzed the developmental regulation of the endocycle and endomitosis, and the contribution of each to SPG size and the blood-brain barrier. We found that during embryogenesis initially all SPG enter the endocycle, but between the first and second larval instar stages the majority of SPG in the brain switch to endomitosis. Notch signaling is required for SPG to remain in the endocycle. To evaluate the functional roles of endomitosis and the endocycle, we reduced Notch signaling and consequently increased the proportion of SPG undergoing endomitosis. Additionally, we generated brains in which all SPG are endocycling by reducing expression of the Cdc25 phosphatase, String. Either of these changes in the ratio of endocycling to endomitotic cells caused defects in the blood-brain barrier. Thus the proper proportion of endocycling and endomitotic SPG is essential, likely to ensure total cell size of the SPG tissue layer to maintain an envelope over the neuronal mass, as we observe that cell size increases disproportionally to ploidy with increasing nuclear number.