Flagella are locomotive organelles present on a wide range of bacteria and are important for the pathogenesis of many species. Cells of the innate immune system lack memory per se, but recognize conserved pathogen-associated molecular patterns (PAMPs) through a family of type I membrane receptors known as Toll-like receptors (TLRs). Flagellin, the major structural component of flagella, is a highly conserved protein recognized in hosts by TLR5. Signaling of flagellin via TLR5/TLR4 heteromeric complexes enhances the diversity of the response, likely by engaging MyD88-independent adaptors to activate the interferon pathway. Flagellin is a potent immune activator, stimulating diverse biologic effects that mediate both innate inflammatory responses as well as the development of adaptive immunity. Binding of flagellin to the extracellular domain of TLR5 rapidly induces a signal cascade that culminates in the production of proinflammatory mediators such as cytokines, chemokines, and costimulatory molecules. This review focuses on the mechanisms of action of flagellin and its effects on both innate and adaptive immunity.