Traumatic brain injuries and their associated treatments carry high cost in both financial impact and morbidity to human life. Recent studies and trials present promising results in reducing secondary injury in the days and weeks following the primary insult. A number of studies, both pre-clinical and clinical, have found that different populations of stem/progenitor cells result in a reduction of inflammation, maintenance of the blood brain barrier, and an overall improved prognosis. The mechanism of action of these cellular therapies appears to rely upon the ability of the cells to influence microglia/macrophage phenotype and alter the state of the inflammatory response. The spleen has become an area of intense interest as an arena where therapeutic cells interact with reactive macrophages to cause system-level changes in immune activity. Additionally, the spleen enacts anti-inflammatory responses originating in the CNS, delivered through vagal activity with a recently described mechanism culminating in acetylcholine release. This review provides a summary of recent findings as to the mechanisms of action observed in current cellular therapies.