The use of numerous mushroom species in traditional medicine has been widely documented, with their observed immunomodulatory effects now attributed, in part, to bioactive components called beta-glucans. The beta-glucans are of particular interest since they are naturally occurring polymers of glucose, are orally active when taken as food supplements and have a long track record of safe use. Due to their immunomodulatory properties, purified beta-glucans have been used clinically as part of a combination therapy for a variety of cancers and their potential anti-infective properties have received attention. This review relates the structure of beta-glucans to their function, with a particular focus on their documented immunomodulatory effects and the mechanisms by which they affect inter- and intracellular function, resulting in potential antimicrobial benefits. Overall, the benefits of dietary supplementation with beta-glucans in order to enhance innate resistance to biological agents are evaluated.