BPD is the most common complication of preterm birth and represents significant morbidity and mortality in the neonatal intensive care unit ( Jobe, 2011 Jobe and Tibboel, 2014). Modelling bronchopulmonary dysplasia (BPD) in experimental animals is a textbook illustration of these concerns. A further confounding variable is the use of experimental animals in medical research, as emphasis must be placed on ‘reduction, refinement and replacement’ (the 3R concept) ( Curzer et al., 2016), where the number of experimental animals employed and the level of stress to which the animal is subjected must be maintained at the minimum level possible, while still retaining the translational viability of the animal model. Furthermore, the precision of the readout that is employed might be inadequate to detect small changes in anatomical structures that are targeted by both the injurious insult and candidate therapeutic intervention. Amongst these, the injurious insult employed in the experimental model might not recapitulate key elements of disease, thereby limiting the ability to evaluate the efficacy of candidate therapeutic agents. Modelling disease pathogenesis in experimental animals is problematic from multiple perspectives. This is particularly evident in animal models of human diseases that are characterised by perturbations to the architecture of an organ. Precise modelling of human disease using animal models is a major challenge in translating bench science to the bedside, as (1) animal models must accurately recapitulate disease processes to facilitate the identification of pathogenic pathways, and (2) animal models represent the limiting step in assessing which therapeutic interventions hold promise for subsequent study. The model presented here, where injurious stimuli have been systematically evaluated, provides a most promising approach for the development of new strategies to drive postnatal lung maturation in affected infants. Thus, a state-of-the-art BPD animal model that recapitulates the two histopathological hallmark perturbations to lung architecture associated with BPD is described. The risk of missing beneficial effects of therapeutic interventions at FiO 2 0.85, using parenteral nutrition as an intervention in the model, was also noted, highlighting the utility of lower FiO 2 in selected studies, and underscoring the need to tailor the model employed to the experimental intervention. Neither a decreasing oxygen gradient (from FiO 2 0.85 to 0.21 over the first 14 days of life) nor an oscillation in FiO 2 (between 0.85 and 0.40 on a 24 h:24 h cycle) had an appreciable impact on lung development. A reduction in FiO 2 to 0.60 or 0.40 also caused a decrease in the total alveoli number, but the septal wall thickness was not impacted. An FiO 2 of 0.85 for the first 14 days of life decreased total alveoli number and concomitantly increased alveolar septal wall thickness, which are two key histopathological characteristics of BPD. The efficacy of a candidate therapeutic intervention using parenteral nutrition was evaluated to demonstrate the utility of the standardised BPD model for drug discovery. Newborn mouse pups were exposed to a varying fraction of oxygen in the inspired air (FiO 2) and a varying window of hyperoxia exposure, after which lung structure was assessed by design-based stereology with systemic uniform random sampling. Our objective was to develop a robust hyperoxia-based mouse model of BPD that recapitulated the pathological perturbations to lung structure noted in infants with BPD. Progress in developing new therapies for bronchopulmonary dysplasia (BPD) is sometimes complicated by the lack of a standardised animal model.