The innate immune system is responsible for a rapid inflammatory response to pathogens that is essential for the clearance of infections. Although this response is vital, it is nonetheless potentially harmful, and dysregulated inflammation is a feature of many disease states. Thus, the mechanisms that regulate the release of soluble mediators of inflammation are an active focus of investigation. The activation by infections of two key components of the innate immune system, the Toll-like receptors (TLRs) and complement, leading to the release of soluble mediators of inflammation, is critical to microbial killing and clearance. Both TLRs and complement are independently capable of triggering pro-inflammatory responses, but their synergistic interaction resulting from a substantial crosstalk markedly amplifies those responses and may contribute to the pathophysiology of diseases such as sepsis.