Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, act cooperatively with the cytokine interferon (IFN)-gamma to induce many of the genes involved in inflammation. In addition, these components synergistically induce secretion of tumor necrosis factor alpha (TNF-alpha), which also synergizes strongly with IFN-gamma. The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors. IFN-gamma-activated signal transducer and activator of transcription 1 and interferon regulatory factor-1 function synergistically with nuclear factor kappaB activated by LPS and TNF-alpha. In addition, cross-talk between the signal transduction pathways upstream of the activation of the transcription factors contributes to generation of the synergistic action. Cooperative activity of proinflammatory agents profoundly influences the immune response to infections and the efficiency of cellular clearance mechanisms.