Children of parents with a mental illness are at significant risk of developing mental disorders and other adverse outcomes at some point in their lives compared to children of healthy parents. During the last 20 years, a comprehensive preventive program for children of parents with a mental illness has been developed in the Netherlands through a longstanding national collaboration between prevention practitioners and scientists. This science- and practice-based program has been implemented by all mental health centres throughout the country (see van Doesum & Hosman, 2009 in this issue). This article describes the scientific underpinnings of this multicomponent program. First, the available epidemiological evidence on risk and the impact on children are discussed, regarding whether parental problems result in similar problems in children (i.e., disorder-synchronous outcomes) or in broad-spectrum outcomes. The article further presents the developmental model of transgenerational transmission of psychopathology and discusses the major mechanisms of risk transmission and the evidence-based risk and protective factors linked to these mechanisms. It finally discusses some implications and future challenges for research, knowledge innovation and implications for program development.