The mucosal immune system is charged with defending the host's vast interfaces with the outside world from the enormous and diverse group of microbes that colonizes these surfaces. A key means by which the mucosal immune system protects the host from such diverse microbes is using germ-line-encoded receptors that target structurally conserved motifs that mediate important bacterial functions. This review focuses on one embodiment of this notion, namely, the mucosal innate immune targeting of flagellin, the primary structural component of flagella, which afford bacteria the ability of directed locomotion. Specifically, we discuss the mechanisms by which flagellin is recognized by the innate immune system, their role in host defense, chronic inflammatory disease, and potential approaches to pharmacologically manipulate these pathways to benefit the host. Discussion will focus on the intestinal tract but will also incorporate key findings in other mucosal surfaces.