CD40L is a type II membrane protein comprised of 261 amino acids. CD40L plays a crucial role in the immune system where it is primarily expressed on activated T cells and triggers immunoglobulin class switching. The genetic disease X-linked hypergammaglobulinemia (HIGM1, XHIGM or XHIM) is caused by mutations in the CD40L gene. Individuals with HIGM1 are susceptible to recurrent infections to pathogens and a relationship has been shown to exist with malaria [Sabeti, P., Usen, S., Farhadian, S., Jallow, M., Doherty, T., Newport, M., Pinder, M., Ward, R., Kwiatkowski, D., 2002a. CD40L association with protection from severe malaria. Genes Immun. 3, 286-291]. In this paper, we phylogenetically examine the promoter region of CD40L in primates and other mammals via phylogenetic shadowing. This analysis revealed several regions of the CD40L promoter that were highly constrained and thereby inferred to be functional. These constrained regions confirmed many known regulatory sites. In addition, a novel, highly constrained upstream region was also identified which had an NF-AT recognition motif. These analyses also showed that the different mammal groups do not share an exactly similar set of promoter binding sites and taxon-specific promoters have evolved.