The major highlights of the current work include that (1) ZIP4 is a novel CSC marker in HGSOC; (2) ZIP4 is a more potent CSC marker than the most extensively characterized ovarian cancer stem cell marker, ALDH, in at least a subset HGSOC; (3) ZIP4 is an upstream regulator of another CSC-marker, NOTCH3, and it physically binds to NOTCH3; (4) NOTCH3 is functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC; and (5) our data suggest that ZIP4 and the novel ZIP4-NOTCH3 axis represent important therapeutic targets in HGSOC. This evidence concerns the gene SLC39A4 and ovarian cancer.