Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. Magnolin inhibits NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Magnolin inhibits the production of tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) by inhibiting extracellular signal-regulated kinases (ERKs), which are key signaling molecules in the regulation of cell proliferation, transformation and cancer cell metastasis. JB6 Cl41 cell migration enhanced by EGF treatment is dramatically suppressed by Magnolin treatment in a dose-dependent manner. Magnolin inhibits ERK1/2/RSK2 signaling-mediated IκBα phosphorylation at Ser32, resulting in the inhibition of NF-κB activation and cell migration.