Adult-onset genetic disorders may present with clinical and magnetic resonance imaging (MRI) features suggestive of acquired inflammatory diseases. An ever-growing number of potentially treatable adult-onset genetic neuroinflammatory disorders have been described in the past few years that need to be rapidly identified. Adult-onset acquired neuroinflammatory disorders encompass a large group of central nervous system (CNS) diseases with varying presentation, MRI characteristics, and course, among which the most common is multiple sclerosis. Despite recent progress, including the discovery of specific autoantibodies, a significant number of adult-onset neuroinflammatory disorders with progressive or relapsing course still remain without a definite diagnosis. In addition, some patients with genetic disorders such as leukodystrophies, hemophagocytic lymphohistiocytosis, or genetic vasculopathies can mimic acquired neuroinflammatory disorders. These genetic disorders, initially described in pediatric populations, are increasingly detected in adulthood thanks to recent progress in molecular genetics and the larger availability of high-throughput sequencing technologies. Genetic adult-onset neuroinflammatory diseases are at the border between primary CNS inflammatory diseases and systemic disorders with multiorgan involvement and predominantly neurologic manifestations. Neurologists must be aware of the main clues and red flags so they can confirm a diagnosis early, when some of these genetic disorders can be successfully treated.