The complement system plays a major role in threat recognition and in orchestrating responses to microbial intruders and accumulating debris. This immune surveillance is largely driven by lectins that sense carbohydrate signatures on foreign, diseased, and healthy host cells and act as complement activators, regulators, or receptors to shape appropriate immune responses. While carbohydrate sensing protects our bodies, misguided or impaired recognition can contribute to disease. Moreover, pathogenic microbes have evolved to evade complement by mimicking host signatures. While complement is recognized as a disease factor, we only slowly start to appreciate the role of carbohydrate interactions in the underlying processes. A better understanding of complement's sweet side will contribute to a better description of disease mechanisms and enhanced diagnostic and therapeutic options. This review introduces the key components in complement-mediated carbohydrate sensing, discusses their role in health and disease, and touches on the potential impact of carbohydrate-related disease intervention.