Neuroendocrine (NE) tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma are metastatic in nature, and secrete biogenic amines and hormones. In this review, we will discuss the possibility that activation of the Ras/Raf signaling pathway may be a therapeutic target for patients with select NE tumors. In-vitro activation of Raf-1 in NE tumors either by expression of the ectopic catalytic domain of Raf-1 or by a pharmacologic drug, ZM336372, resulted in growth inhibition. In addition, activation of the Ras/Raf pathway led to a significant reduction in NE markers such as serotonin, chromogranin A and calcitonin. These data support development of Raf-1-activating compounds for treatment of patients with NE tumors of selective subtypes. © 2006 Lippincott Williams & Wilkins.