Diagnostic and prognostic uncertainty is one of the major psychological stressors for patients in acute and chronic illness, as well as for parents of children with disabilities or chronic disease. Whereas the parents' feeling of uncertainty is undoubtedly very strong shortly after the birth of a child with disabilities, the long-term effects on the parents of having or not having a precise genetic diagnosis, in terms of emotional stress, remain unclear. In this study, mothers of non-disabled children are compared to mothers of children with Down syndrome, and to mothers of children with a diagnostically unassigned mental retardation with regard to the level of anxiety, feelings of guilt, and emotional burden. While the mothers of children with Down syndrome score comparably to the mothers of non-disabled children, the results show broad psychoemotional disadvantages for mothers of children with a mental retardation of unknown etiology. Consequently, the value of genetic diagnosis of infantile disabilities encompasses, beyond clinical considerations like therapy planning and assignment of the recurrence risk for siblings, significant and long-lasting emotional relief for the parents. © 2005 Wiley-Liss, Inc.