SummaryEpilepsy is one of the more prevalent neurologic disorders in the world, affecting approximately 50 million people of different ages and backgrounds. Epileptic seizures propagating through both lobes of the forebrain can have permanent debilitating effects on a patient's cognitive and somatosensory brain functions. Epilepsy, defined by the sporadic occurrence of spontaneous recurrent seizures (SRS), is often accompanied by inflammation of the brain. Pronounced increases in the expression of key inflammatory mediators (e.g., interleukin ‐1β [IL‐1β], tumor necrosis factor alpha [TNFα], cyclooxygenase‐2 [COX‐2], and C‐X‐C motif chemokine 10 [CXCL10]) after seizures may cause secondary damage in the brain and increase the likelihood of repetitive seizures. TheCOX‐2 enzyme is induced rapidly during seizures. The increased level ofCOX‐2 in specific areas of the epileptic brain can help to identify regions of seizure‐induced brain inflammation. A good deal of effort has been expended to determine whetherCOX‐2 inhibition might be neuroprotective and represent an adjunct therapeutic strategy along with antiepileptic drugs used to treat epilepsy. However, the effectiveness ofCOX‐2 inhibitors on epilepsy animal models appears to depend on the timing of administration. With all of the effort placed on making use ofCOX‐2 inhibitors as therapeutic agents for the treatment of epilepsy, inflammation, and neurodegenerative diseases there has yet to be a selective and potentCOX‐2 inhibitor that has shown a clear therapeutic outcome with acceptable side effects.