Members of the Toll-like receptor (TLR) family play critical roles as regulators of innate and adaptive immune responses. TLRs function by recognizing diverse molecular patterns on the surface of invading pathogens. In the brain, microglial cells generate neuroimmune responses through production of proinflammatory mediators. The upregulation of cytokines and chemokines in response to microbial products and other stimuli has both beneficial and deleterious effects. Emerging evidence demonstrates a central role for TLRs expressed on microglia as a pivotal factor in generating these neuroimmune responses. Therefore, understanding the basis of TLR signaling in producing these responses may provide insights into how activated microglia attempt to strike a balance between defense against invading pathogens and inflicting irreparable brain damage. These insights may lead to innovative therapies for CNS infections and neuroinflammatory diseases based on the modulation of microglial cell activation through TLR signaling.