Acquired demyelinating disorders lead to overlapping visual, pyramidal, sensory, autonomic, and cerebellar deficits and may lead to severe disability. Early diagnosis and start of treatment are fundamental towards preventing further attacks and halting disability. In this paper we provide an updated overview of the differential diagnoses of acquired demyelinating disorders. We performed a critical targeted review of the diagnoses of the most prevalent demyelinating disorders: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). We discuss the workup, diagnostic criteria and new biomarkers currently being used for the diagnosis of these disease entities taking into account the particularities of the Brazilian population and healthcare system. A comprehensive analysis of medical history, physical examination, biomedical and imaging data should be performed to obtain differential diagnosis. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.