The spectrum of post infectious (PI) central nervous system (CNS) conditions includes a range of grey and white-matter disorders which can occur after viral or bacterial infections or in response to vaccinations. The clinical, radiological and immunological phenomenology raises a number of issues regarding the nature of immune-mediated CNS abnormalities, their etiology, pathogenesis and therapy. Here we focus on crucial issues pertaining to pathogenesis and aim to identify where current knowledge is insufficient in order to suggest future avenues of clinical and experimental research that may help to devise optimal therapy for these conditions.