It is now widely accepted that cystic fibrosis (CF) lung disease begins in infancy and early childhood, with evidence of structural, functional, and inflammatory changes present even in asymptomatic children. This realization, coupled with broad adoption of CF newborn screening in the United States, Canada, Europe, and Australia, has raised the possibility for primary prevention of CF lung disease. To intervene before respiratory symptoms develop in infants and preschool children with CF, sensitive testing modalities are necessary to define and follow mild CF lung disease, both for research and for clinical purposes. Ideal testing would be sensitive to early heterogeneous disease located in the peripheral airways, able to detect small changes in disease (either progression or therapeutic response), easy to perform without sedation, and safe for repeated measures. This article will review existing and novel modalities for identification of CF lung disease in infancy and early childhood, focusing on pulmonary function testing, structural imaging, identification of infectious pathogens, and detection of inflammation.