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MAPK pathways play a critical role in the activation of monocytes and macrophages by pathogens, signaling molecules and environmental cues and in the regulation of macrophage function and plasticity. MAPK phosphatase 1 (MKP-1) has emerged as the main counter-regulator of MAPK signaling in monocytes and macrophages. Loss of MKP-1 in monocytes and macrophages in response to metabolic stress leads to dysregulation of monocyte adhesion and migration, and gives rise to dysfunctional, proatherogenic monocyte-derived macrophages. Here we review the properties of this redox-regulated dual-specificity MAPK phosphatase and the role of MKP-1 in monocyte and macrophage biology and cardiovascular diseases.MKP-1 is a critical counter-regulator of MAPK signaling in monocytes and macrophages.MKP-1 regulates monocyte adhesion and migration.MKP-1 regulates macrophage activation, inflammatory responses and survival.MKP-1 activity is regulated at the level of transcription, translation and by posttranslational modifications.