Here, we demonstrate the first evidence that the transcription factor/oncogene FOXM1 forms a protein complex with a serine/threonine kinase MELK and that FOXM1 serves as a substrate of MELK in cancer cells, and MELK-regulated FOXM1 phosphorylation controls FOXM1 activity and induces the expression of downstream mitotic regulators. Here, FOXM1 is linked to cancer.