The present study analyzes differences in parental stress in families of children with Down, Williams, Fragile X, and Prader-Willi syndromes, exploring factors that influence parental stress, such as child's characteristics, parental locus of control, and family cohesion and adaptability. Differences between mothers and fathers are also investigated. Parents were given self-report questionnaires to assess family stress, parental locus of control, and family cohesion and adaptability. Results showed that stress levels were lower in families of children with Down syndrome and higher in those of children with Prader-Willi syndrome. Children's characteristics and their parents' locus of control were found to be related to family stress levels in all four syndromes, but several aspects specific to a given syndrome also came to light, as well as some shared and some gender-specific features relating to mothers and fathers.