Zebrafish (Danio rerio) have become a powerful tool in neuroscience research due to their genetic tractability, molecular/physiological conservation, small body size, ease of experimental manipulations in vivo, and rich behavioral repertoire. Zebrafish models and tests are particularly useful in genetics research, neurophenotyping, CNS drug screening, as well as in modeling complex neurological and psychiatric disorders. Here, we discuss selected examples of successful application of zebrafish models to mimicking various aspects of brain pathology, and emphasize their developing utility for studying the underlying molecular and genetic mechanisms. We also summarize recent advances in zebrafish-based CNS disease modeling, and outline new research strategies that may significantly improve translational neuroscience and experimental neurology research, and drug discovery.