Mitogen-activated protein (MAP)(§) kinase cascades are crucial signal transduction pathways in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the feedback control of p38 and JNK. In vitro studies using cultured macrophages have provided strong evidence for a critical role of MKP-1 in the restraint of pro-inflammatory cytokine biosynthesis. Recently, a number of studies conducted using MKP-1 knockout mice have verified the importance of MKP-1 in the regulation of p38 and JNK and in the regulation of pro-inflammatory cytokine synthesis. Upon lipopolysaccharide challenge MKP-1 knockout mice produced dramatically greater amounts of inflammatory cytokines, developed severe hypotension, and multi-organ failure, and exhibited a remarkable increase in mortality. These studies demonstrate that MKP-1 is an essential feedback regulator of the innate immune response, and that it plays a critical role in preventing septic shock and multi-organ dysfunction during pathogenic infection.