We demonstrate that mitogen-activated protein kinase–activated kinase-2 (MK2) is essential for localized Th2-type inflammation and development of experimental asthma. MK2 deficiency does not affect systemic Th2 immunity, but reduces endothelial permeability, as well as adhesion molecule and chemokine expression. NF-κB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-κB activation. MK2 and HSP27 prevent nuclear retention of p38 by sequestering it in the cytosol. As a result, MK2 precludes excessive phosphorylation of MSK1. By reducing MSK1 activity, MK2 prevents p65 NF-κB hyperphosphorylation and excessive IκBα transcription. IκBα mediates nuclear export of p65. By reducing IκBα level, MK2 prevents premature export of NF-κB from the nucleus. Thus, the MK2–HSP27 pathway regulates the NF-κB transcriptional output by switching the activation pattern from high level, but short lasting, to moderate-level, but long lasting. This pattern of activation is essential for many NF-κB–regulated genes and development of inflammation. Thus, the MK2–HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases.