Activation of antigen‐presenting cells (APCs) by invariant constituents of pathogens such as lipopolysaccharide (LPS) or bacterial DNA (CpG‐DNA) initiates immune responses. We have analyzed the mitogen‐activated protein kinase (MAPK) pathways triggered by CpG‐DNA and their significance for cytokine production in two subsets of APCs, ie macrophages and dendritic cells (DCs). We found that CpG‐DNA induced extracellular signal‐regulated kinase (ERK) activity in macrophages in a classic MEK‐dependent way. This pathway up‐regulated tumor necrosis factor production but down‐regulated interleukin (IL)‐12 production. However, in DCs, which produce large amounts of IL‐12, CpG‐DNA and LPS failed to induce ERK activity. Consistent with a specific negative regulatory role for ERK in macrophages, chemical activation of this pathway in DCs suppressed CpG‐DNA‐induced IL‐12 production. Overall, these results imply that differential activation of MAP kinase pathways is a basic mechanism by which distinct subsets of innate immune cells regulate their effector functions.