This article discusses the importance of and one approach to translational research to prevent internalizing problems very early in life. The World Health Organisation (WHO) predicts that by 2,030 internalizing problems will be second only to HIV/AIDS in the international burden of disease. Internalizing problems affect one in every seven school age children, with negative impacts on peer relations, school engagement, and later mental health, adult relationships, and employment. There is persuasive evidence that intervention in the preschool years can have a cost-effective impact on general developmental outcomes, compared to later school or adult intervention. However, the development of early childhood prevention for internalizing problems is in its infancy. Two significant risk factors for child internalizing problems are temperamental inhibition (characterized by fearfulness and withdrawal) and overinvolved/protective parenting practices. Rapee et al. have conducted two randomized “efficacy” trials with inhibited preschoolers in which a parenting group intervention reduced internalizing disorders up to 3 years later. Translational “effectiveness” research is now underway at the population level, to determine the balance of benefits and harms of systematically screening preschoolers for inhibition and subsequent intervention for all those affected. This rigorous public health research, followed by effective dissemination, addresses gaps identified in the WHO Prevention of Mental Disorders report. Depression and Anxiety 0:1–8, 2010.© 2010 Wiley-Liss, Inc.