Over the last 2 decades, numerous innate inflammatory mediators have been reported to be upregulated in pathologically vulnerable regions of the brain in Alzheimer's disease (AD). These data have led to a reexamination of the dogma of brain immunologic privilege and to new studies that examine the role of the innate inflammatory response in a number of other neurologic disorders, particularly Parkinson's disease and human immunodeficiency virus dementia. In addition, basic science discoveries about neuroinflammation are now beginning to move to the clinic. More than 20 epidemiologic surveys have consistently demonstrated that common non-steroidal anti-inflammatory drugs may protect against the development of AD. By contrast, anti-inflammatory treatment trials for existing AD have typically shown little to no effect on halting or reversing the disorder, although the agents tested have often been at odds with those suggested by the epidemiologic and basic science results. The extensive literature on innate inflammation and neurologic disease notwithstanding, three fundamental questions still remain to be answered fully. First, are innate inflammatory responses a cause of neurologic disease or merely a more sophisticated means than previously imagined for removing the detritus left by more primary pathogenic mechanisms? Second, can anti-inflammatory agents effectively treat existing neurologic disease, or is a protective strategy in high-risk patients the only reasonable option? Third, whether for protection or treatment, what is the best choice of anti-inflammatory agent given the basic science mechanisms and epidemiologic results that have been reported?