The orientation of mitotic spindles, which determines the plane of cell division, is tightly regulated in polarized cells such as epithelial cells, but it has been unclear whether there is a mechanism regulating spindle orientation in non-polarized cultured cells. In adherent cultured cells, spindles are positioned at the center of the cells and the axis of the spindle lies in the longest axis of the cell. Thus, cell geometry is thought to be one of cues for spindle orientation and positioning in cultured cells because this defines the center and the long axis of the cell. Recent work provides a new insight into the spindle orientation in cultured cells; spindles are aligned along the axis parallel to the cell-substrate adhesion plane. Concomitantly, integrin-mediated cell adhesion to the extracellular matrix (ECM), rather than gravitation, cell-cell adhesion or cell geometry, has shown to be essential for this mechanism of spindle orientation. Several independent lines of evidence confirm the involvement of cell-ECM adhesion in spindle orientation in both cultured cells and in developing organisms. The important future challenge is to identify a molecular mechanism(s) that links integrin and spindles in the control of spindle axis.