Signaling through extracellular signal-regulated kinase (ERK) is important in multiple signal transduction networks in the CNS. However, the specific role of ERK2 inin vivobrain functions is not fully understood. Here we show that ERK2 play a critical role in regulating social behaviors as well as cognitive and emotional behaviors in mice. To study the brain function of ERK2, we used a conditional, region-specific, genetic approach to targetErk2using the Cre/loxP strategy with anestinpromoter-drivencretransgenic mouse line to induce recombination in the CNS. The resultingErk2conditional knock-out (CKO) mice, in whichErk2was abrogated specifically in the CNS, were viable and fertile with a normal appearance. These mice, however, exhibited marked anomalies in multiple aspects of social behaviors related to facets of autism-spectrum disorders: elevated aggressive behaviors, deficits in maternal nurturing, poor nest-building, and lower levels of social familiarity and social interaction.Erk2CKO mice also exhibited decreased anxiety-related behaviors and impaired long-term memory. Pharmacological inhibition of ERK1 phosphorylation inErk2CKO mice did not affect the impairments in social behaviors and learning disabilities, indicating that ERK2, but not ERK1 plays a critical role in these behaviors. Our findings suggest that ERK2 has complex and multiple roles in the CNS, with important implications for human psychiatric disorders characterized by deficits in social behaviors.