Protein tyrosine phosphatases (PTPs) act to oppose the action of tyrosine kinases and serve important roles in regulating levels of phosphotyrosine in cells. Accumulating evidence points to the roles of PTPs in neuronal development and function, as well as neurotransmitter and growth factor receptor signaling cascades. By analogy to the family of tyrosine kinases, there are both receptor-like and intracellular tyrosine phosphatases. A number of these have been identified in the brain and found to be nervous system-enriched. This article describes brain-enriched PTPs, their localization patterns in brain, and speculations regarding their functional roles.