Growth arrest and DNA damage-inducible [beta] ("Gadd45b") has been shown to be involved in DNA demethylation and may be important for cognitive processes. "Gadd45b" is abnormally expressed in subjects with autism and psychosis, two disorders associated with cognitive deficits. Furthermore, several high-throughput screens have identified "Gadd45b" as a candidate plasticity-related gene. However, a direct demonstration of a link between "Gadd45b" and memory has not been established. The current studies first determined whether expression of the "Gadd45" family of genes was affected by contextual fear conditioning. "Gadd45b", and to a lesser extent "Gadd45g", were up-regulated in the hippocampus following contextual fear conditioning, whereas "Gadd45a" was not. Next, "Gadd45b" knockout mice were tested for contextual and cued fear conditioning. "Gadd45b" knockout mice exhibited a significant deficit in long-term contextual fear conditioning; however, they displayed normal levels of short-term contextual fear conditioning. No differences between "Gadd45b" knockout and wild-type mice were observed in cued fear conditioning. Because cued fear conditioning is hippocampus independent, while contextual fear conditioning is hippocampus dependent, the current studies suggest that "Gadd45b" may be important for long-term hippocampus-dependent memory storage. Therefore, "Gadd45b" may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders.