Clinical tissue analyses and functional models indicate that NGF is upregulated in osteosarcoma and enhances migratory and invasive programs through TrkA–MEK/ERK–MMP−2 signaling; pharmacologic interruption of Trk or MEK/ERK signaling reverses these phenotypes and limits metastatic traits in preclinical systems. The gene discussed is NTRK1; the disease is osteosarcoma.