The downstream signaling pathways include the Rat sarcoma (Ras), mitogen activated protein (MAP), extracellular signal regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), Akt, Janus activated kinase (JAK3) and Signal Transducer and Activator of Transcription (STAT3) signaling pathways. In general, the RAS/MEK/ERK pathway drives cell proliferation, and the PI3K/Akt and JAK3-STAT3 pathways play pro-survival roles. Although different ALK fusions may differentially activate downstream signaling pathways, EML4-ALK signals through ERK and PI3K. Activation of the RAS/MEK/ERK and PI3K/Akt pathways play key roles in EML4-ALK–mediated cellular oncogenesis.