Determining the cause of myelitis and distinguishing inflammatory from non-inflammatory etiologies is crucial as without early disease specific-treatment, morbidity can develop quickly and be irreversible. Recent studies have shown that large proportions of patients referred with idiopathic transverse myelitis actually have a specific cause identified for their myelopathy. Thus, idiopathic transverse myelitis is a diagnosis of exclusion and requires a comprehensive evaluation for alternative etiologies prior to assigning this diagnosis. The increasing number of specific causes of myelopathy/myelitis identified over the last two decades has made evaluation of such patients more challenging. This course will focus on demographic, clinical, serologic, and radiologic pearls that can help determine the cause of myelitis. We will also briefly review acute treatment. Determining the speed of onset and time to nadir is very helpful in narrowing the differential diagnosis of myelopathies. Improved recognition of the MRI features of myelopathies, particularly the gadolinium enhancement patterns, can give a clue to the diagnosis. The identification of diagnostic autoantibody biomarkers of myelitis (e.g., Aquaporin-4-IgG and Myelin Oligodendrocyte Glycoprotein-IgG IgG) has led to major improvements in our understanding of its underlying mechanisms and allowed their distinction from MS and other etiologies. Moreover, they have provided insight into the risk of recurrence, likelihood of treatment response and long-term outcome. Ancillary investigations including brain MRI are useful and may help determine the underlying cause (e.g., identification of typical multiple sclerosis lesions). The frequency of infectious myelitis varies by location and outbreaks of acute flaccid myelitis associated with enterovirus D69 are recognized to occur in children and should be specifically considered in endemic regions. The acute treatment of transverse myelitis associated with central nervous system inflammatory demyelinating diseases typically includes high-dose intravenous steroids with the addition of plasmapheresis in those with residual deficits. In conclusion, myelitis has a broad differential diagnosis and using the demographic, clinical, radiologic and serologic features can help determine the diagnosis and guide treatment.