The Clinic for Special Children in Lancaster County, Pennsylvania, is a community-supported, nonprofit pediatric medical practice for Amish and Mennonite children who have genetic disorders. Over a 14-year period, 1988-2002, we have encountered 39 heritable disorders among the Amish and 23 among the Mennonites. We emphasize early recognition and long-term medical care of children with genetic conditions. In the clinic laboratory we perform amino acid analyses by high-performance liquid chromatography (HPLC), organic acid analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by polymerase chain reaction (PCR) amplification and sequencing or restriction digestion. Regional hospitals and midwives routinely send whole-blood filter paper neonatal screens for tandem mass spectrometry and other modern analytical methods to detect 14 of the metabolic disorders found in these populations as part of the NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease pathophysiology reduces morbidity, mortality, and costs for the majority of disorders. Among our patients who are homozygous for the same mutation, differences in disease severity are not unusual. Clinical problems typically arise from the interaction of the underlying genetic disorder with common infections, malnutrition, injuries, and immune dysfunction that act through classical pathophysiological disease mechanisms to influence the natural history of disease.