Although the zebrafish (Danio rerio) has been used extensively for many years in neurodevelopmental studies, use of this teleost to study neurological diseases has evolved only recently. Being a vertebrate, this animal offers advantages for the study of human disease over other small animals, such as the fly or worm. Genetic, as well as nongenetic, disorders can be modeled in both the adult organism and the embryo. Genetic manipulation of the embryo to generate stable and transiently expressing transgenic fish, and to knockdown genes to study loss of their function, can be easily achieved. Because of large offspring numbers screening studies can also be readily performed. Here, we describe some of the protocols useful for modeling neurodegenerative disease in zebrafish embryos, with particular emphasis on models to study motor neuron phenotypes.