Wnt proteins are members of the highly conserved wingless family of proteins responsible for cell differentiation and development and for neoplastic and degenerative processes. Recently, Toll-like receptor-mediated Wnt signaling was found to be associated with innate immunity in Drosophila. Upregulation of Wnt5A in human macrophages upon microbial challenge indicated a similar mechanism. Toll-like receptor-mediated Wnt5A expression is a key process for sustained inflammatory macrophage activation through autocrine and paracrine signaling. Downregulation of Wnt5A expression and subsequent attenuation of inflammatory macrophage responses by activated protein C supports the link between inflammation and coagulation, another highly conserved biologic system. Direct evidence for the relevance of Wnt5A in severe systemic inflammation is provided by the finding of higher Wnt5A levels in patients with sepsis than in healthy individuals. The fact that Wnt5A signaling can be modulated by anti-inflammatory mediators makes this effector molecule an attractive target for therapeutic intervention in inflammatory diseases.