Although the premature loss of primary teeth in conjunction with early eruption may be of no clinical significance, the loss of primary or permanent teeth in the absence of trauma should not be overlooked by the clinician. Premature loss of teeth associated with systemic disease usually results from some change in the immune system or connective tissue. This chapter presented some conditions associated with loosening and/or premature loss of teeth that may be encountered in children and adolescents. The most common of these conditions appear to be hypophosphatasia and early-onset periodontitis. Other less common conditions were described to aid in forming a differential diagnosis. Other diseases that may manifest with severe oral infection, such as Wiskott-Aldrich syndrome, diabetes mellitus, or herpes zoster, could result in early tooth loss.