β-Glucans are cell wall constituents of many plants and microorganisms. However, β-glucans are not expressed on mammalian cells and are recognized as pathogen-associated molecular patterns by pattern recognition receptors. β- Glucans have been used to treat cancer and infectious disease for many years as biological response modifiers with varying and unpredictable efficacy. Recent studies have demonstrated the mechanism of action of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies in cancer therapy. in vitro and in vivo Data indicate that successful combination therapy requires complement activation and iC3b deposition on tumors and complement receptor 3 (CR3) expression on granulocytes. The defined effector cells are CR3+ neutrophils. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and receptors, mechanism of action, and preclinical studies in human carcinoma xenograft models. Current and future developments are also discussed to provide our own point of view on this combination therapy in potential clinical investigations. Relevant patents are discussed.