The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system. We found that B. anthracis lethal factor (LF) selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs. Because macrophages that are deficient in transcription factor nuclear factor κB (NF-κB) are also sensitive to activation-induced death and p38 is required for expression of certain NF-κB target genes, p38 is probably essential for synergistic induction of those NF-κB target genes that prevent apoptosis of activated macrophages. This dismantling of the p38 MAPK module represents a strategy used by B. anthracis to paralyze host innate immunity.