Yeast-derived beta-glucans (Y-BG) are considered immunomodulatory compounds suggested to enhance the defense against infections and exert anticarcinogenic effects. Specific preparations have received Generally Recognized as Safe status and acceptance as novel food ingredients by European Food Safety Authority. In human trials, orally administered Y-BG significantly reduced the incidence of upper respiratory tract infections in individuals susceptible to upper respiratory tract infections, whereas significant differences were not seen in healthy individuals. Increased salivary IgA in healthy individuals, increased IL-10 levels in obese subjects, beneficial changes in immunological parameters in allergic patients, and activated monocytes in cancer patients have been reported following Y-BG intake. The studies were conducted with different doses (7.5–1500 mg/day), using different preparations that vary in their primary structure, molecular weight, and solubility. In animal models, oral Y-BG have reduced the incidence of bacterial infections and levels of stress-induced cytokines and enhanced antineoplastic effects of cytotoxic agents. Protective effects toward drug intoxication and ischemia/reperfusion injury have also been reported. In conclusion, additional studies following good clinical practice principles are needed in which well-defined Y-BG preparations are used and immune markers and disease endpoints are assessed. Since optimal dosing may depend on preparation characteristics, dose-response curves might be assessed to find the optimal dose for a specific preparation.