Herpes simplex encephalitis is a devastating neurological disorder with a poor prognosis. For years, it remained elusive why a fraction of otherwise healthy individuals presented with the condition; this lack of insight has hampered understanding of disease pathogenesis and the development of novel effective therapies. However, recent studies have shown that the lack of viral containment can be caused by functionally related monogenic inborn errors of immunity at least in a subset of patients. This knowledge renders prophylactic measures and design of targeted therapies possible, as argued in this review.