Multiple Sclerosis (MS), the most common disabling neurological disease affecting young adults in developed countries, is a complex genetic disease associated with both environmental and genetic risk factors. In most cases, the risk factors’ individual associations with MS are so weak that any meaningful understanding of the disease will require the identification of molecular pathways that contribute to MS liability. We therefore hypothesised that the complex genetic phenotype is driven by a co-ordinated expression of transcriptional regulatory networks.  To test this, we generated a weighted gene co-expression network based on 712 pooled Affymetrix Human Gene 1.0 ST array analyses of magnetic bead sorted B cells, CD4 and CD8 T cells, NK cells and monocytes, from 67 untreated relapsing/remitting MS patients and 102 Healthy Controls (HC). Sixteen relatively independent gene modules were identified. For each leukocyte population, the strength of differential expression between patients and HC was assessed, by ranking genes by Mann Whitney U test and ANOVA, and each transcript was tested across the network to identify modules of interest. A major networked module of genes involved in cell-mediated cytotoxicity that is downregulated in the monocytes and NK cells of MS patients was identified. Both in vitro and in vivo approaches were taken to elucidate the role of this module in MS and EAE. Here we have identified three genes, that when modulated, affect expression of many genes within this module. In addition, their targeted deletion results in more severe EAE. Further dissection of this “killer module” and the elucidation of its role in MS and EAE may thus provide a new perspective on the aetiology of, not only MS but, other complex autoimmune diseases and thereby offer novel interventions.