During infection or inflammation, the expression of cytochrome P450 and its dependent biotransformation pathways are modified. This results in a change in the capacity of the liver to handle drugs and in alterations in the production and elimination of endogenous substances throughout the body. The majority of the CYP isoforms are modified at pre-translational steps in protein synthesis, and, in most cases, cytokines are involved as mediators of the response. Recent information suggests that inflammatory responses that are localized to the CNS cause a loss of CYP within the brain. This is accompanied by a parallel down-regulation of CYP in peripheral organs that is mediated by a signaling pathway between the brain and periphery. This review covers the loss that occurs in the major mammalian CYP families in response to infection/inflammation and the mediator pathways that are key to this response.