Background: The current study focuses on mothers and fathers of children with three rare genetic syndromes that are relatively unexplored in terms of family experience: Angelman syndrome, Cornelia de Lange syndrome and Cri du Chat syndrome. Method: Parents of children with Angelman syndrome (n = 15), Cornelia de Lange syndrome (n = 16) and Cri du Chat syndrome (n = 18), and a matched comparison group of parents of children with autism and intellectual disabilities (n = 20) completed questionnaires on both psychological distress (stress, anxiety, depression) and positive psychological functioning. Results: Parents of children with Angelman syndrome consistently reported the highest levels of psychological distress, and parents of children with Cornelia de Lange syndrome the lowest, with parents of children with Cri du Chat syndrome and autism scoring between these two. Positive psychological functioning was similar across the four aetiology groups. Conclusions: Parents of children with rare genetic syndromes are at risk for high levels of stress and mental health problems. Methodological issues and the practical applications of these results are discussed.