Acute flaccid myelitis (AFM) is a sudden-onset polio-like neuromuscular disability found commonly in young children. There is an increasing incidence of confirmed AFM cases in the USA and other countries in recent years, and in association with nonpolio enterovirus infection. This represents a significant challenge to clinicians and causes significant concern to the general public. Acute flaccid paralysis (AFP) is the long-known limb paralytic syndrome caused by a viral pathogen. AFM is a subset of AFP that is also characterized by a limb paralytic condition, but it has certain distinct features such as lesions in magnetic resonance imaging of the spinal cord gray matter. AFM leads to spinal cord, brainstem, or motor neuron dysfunction. The clinical phenotypes, pathology, and patient presentation of AFM closely mimic AFP. This article provides a concise overview of our current understanding of AFM and the clinical features that distinguish AFM from AFP and similar other neurological infectious and autoimmune diseases or disorders. We also discuss the diagnosis, clinical pathology, possible pathogenetic mechanisms, and currently available therapies.