Specialization of the cell-division process is a common feature of developing embryos, but most studies on vertebrate cell division have focused on cells dividing in culture. Here, we used in vivo four-dimensional confocal microscopy to explore the role of Cdc42 in governing cell division in the developing neural epithelium of Xenopus laevis. We find that Cdc42 is crucial for stable positioning of the metaphase spindle in these cells, but was not required for spindle positioning in epidermal epithelial cells. We also find that divisions in the Xenopus neural plate are planar oriented, and that rotations of mitotic spindles are essential for establishing this orientation. When Cdc42 is disrupted, spindles over-rotate and the final orientation of divisions is changed. Finally, the planar orientation of cell divisions in this tissue seems to be independent of planar cell polarity (PCP) signaling and does not require normal neural morphogenesis. Our data provide new insights into the coordination of cell division and morphogenesis in epithelial cell sheets and reveal novel, cell-type-specific roles for Cdc42 in spindle positioning and spindle orientation.