The presentation of a patient with brainstem symptoms and signs invokes a number of common and less common differential diagnoses, and accurate diagnosis can be challenging. We review the major immune-mediated and inflammatory syndromes that can affect the brainstem including multiple sclerosis, neuromyelitis optica spectrum disorder, neuro-Behcet’s disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, neurosarcoidosis, Susac’s syndrome and the histiocytic disorders. We focus on clinical features and magnetic resonance imaging clues that help to distinguish between the different brainstem conditions. Accurate diagnosis is important to guide appropriate treatment and limit neurological disability.