Neurotrophins play important roles in neuronal survival during vertebrate development. Neurotrophin-4 (NT4), alone or in combination with brain-derived neurotrophic factor (BDNF), has been suggested to be necessary for the survival of peripheral sensory neurons and central nervous system (CNS) neurons, including motor neurons. To define the role of NT4 in vivo, we generated mice lacking NT4 by gene targeting. NT4-deficient mice were viable but exhibited a loss of sensory neurons in the nodose-petrosal and geniculate ganglia. In contrast, motor neurons of the facial nucleus and sympathetic neurons of the superior cervical ganglion were unaffected, and there was no obvious loss of dopaminergic neurons in the substantia nigra. In mice lacking both NT4 and BDNF, facial neurons remained unaffected, whereas the loss of sensory neurons was more severe than with either mutation alone. Thus NT4 is required during development for the survival of some peripheral sensory neurons but not sympathetic or motor neurons.