Tolerance to lipopolysaccharide (LPS) is part of the host's strategy to avoid harmful excessive inflammation in the presence of Gram-negative commensals and pathogens. Macrophages are the major cells endowed with this property, allowing them to limit expression of proinflammatory genes while maintaining efficient antimicrobial functions. In a recent paper, Foster et al. (2007) demonstrate that this subtle balance is established and imprinted via epigenetic regulation.