DNA methylation is thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a pathogenic bacteria is associated with rapid changes in methylation at thousands of loci. Infection-induced changes in methylation occur primarily at distal enhancer elements, including those associated with the activation of key immune transcription factors and genes involved in the crosstalk between DCs and adaptive immunity. Active demethylation is associated with extensive epigenetic remodeling and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that rapid changes in methylation play a previously unappreciated role in regulating the transcriptional response of DCs to infection.