Pathogenic Acanthamoeba are known to infect the CNS, resulting in fatal granulomatous encephalitis. The mechanisms associated with the pathogenesis remain unclear; however pathophysiological complications involving the CNS most likely include induction of pro-inflammatory responses, invasion of the blood-brain barrier and the connective tissue and neuronal damage leading to brain dysfunction. The routes of entry include the olfactory neuroepithelium pathway and/or lower respiratory tract, followed by haematogenous spread. Skin lesions may provide direct entry into the bloodstream, bypassing the lower respiratory tract. For the haematogenous route, entry of amoebae into the CNS most likely occurs at the sites of the blood-brain barrier. Recent studies have identified several molecular mechanisms associated with Acanthamoeba traversal of the blood-brain barrier and targeting those may help develop therapeutic interventions and/or design preventative strategies.