Marine natural products show a large variety of unique chemical structures and potent biological activities. Elucidating the target molecule and the mechanism of action is an essential and challenging step in drug development starting with a natural product. Odoamide, a member of aurilide-family isolated from Okinawan marine cyanobacterium, has been known to exhibit highly potent cytotoxicity against various cancer cell lines. In this study, we investigated the target protein and the cytotoxic mechanism of odoamide. Compared to existing anticancer agents, odoamide showed a unique fingerprint in the JFCR39 cancer cell panel and a characteristic pattern in gene expression profiling. Affinity chromatography utilizing a biologically active odoamide probe identified ATPase Na