A successful response to pathogen challenge requires that a balance is achieved between the induction of efficient anti-microbial effector mechanisms and the avoidance of detrimental tissue damage. While the Toll-like receptor (TLR) system is innate immunity's sensor of infectious danger, macrophages receive activating as well as inhibitory signals via the Jak-Stat pathway. IFNgamma is key to the control of infection particularly with intracellular pathogens and depends on functional Stat1 signal transduction. Stat3 signalling is activated by a range of cytokines, including IL-10, IL-6 and IL-27. Here, recent progress in understanding the regulation of macrophage function in inflammation and infection by Stat3-activating cytokines is reviewed. The use of targeted mouse mutants of these cytokines, their receptors or signalling components, revealed the importance of the Stat3 axis in the control of infection and immunopathology. Genome-wide transcriptome analyses of macrophages under the influence of these cytokines have contributed to advances in defining the molecular mechanisms of macrophage activation and deactivation. Functional characterization of Stat3-target genes should now identify the molecular mediators of impaired pathogen control and tissue protection.