This chapter reviews an important mediator and its associated factors, the Toll-like receptors (TLRs). It examines the possible role that TLRs serve in neuroimmune interactions within both the central and peripheral nervous systems. The chapter focuses on Toll-like receptor 4 (TLR4) as this TLR appears to contribute directly to neurological pathologies such as neuropathic pain and opioid-induced hyperalgesia, as well as epilepsy. Inflammation in the absence of infection contributes to both injury and disease processes in the nervous system. There are many similarities between the mediators and changes in synaptic connectivity between neuropathic pain and epilepsy. Epileptic seizure conditions are routinely characterized as a neurocentric disease due in large part to the abnormally excessive or synchronous neuronal activity in the brain. The opioid family of drugs, though potent analgesics, are known to be only partially effective in treating neuropathic pain due in large part to the myriad of side effects.