Local and systemic inflammatory responses have been shown to play an important role in post-stroke damage. Recent studies suggest that the innate immune cells contribute to stroke-induced brain injury by activating an inflammatory response that further increases local ischemic damage. Innate immune signaling, via Toll-like receptors (TLRs), has been shown to be involved in several neuropathological processes. This chapter summarizes the current knowledge concerning the involvement of TLRs in acute ischemic brain injury. In particular, the therapeutic role of TLR2 and TLR4 antagonists will be discussed. Moreover, since TLR3 stimulation could play a beneficial role through the production of anti-inflammatory molecules, including I type interferons (IFNs), the potential benefits of TLR3 agonist administration to counteract stroke-related inflammation will be also focused.