BACKGROUND: The rates of major neonatal morbidities, such as bronchopulmonary dysplasia, necrotizing enterocolitis, preterm white matter disease, and retinopathy of prematurity, remain high among surviving preterm infants. Exposure to inflammatory stimuli and the subsequent host innate immune response contribute to the risk of developing these complications of prematurity. Notably, the burden of inflammation and associated neonatal morbidity is inversely related to gestational age - leaving primarily but not exclusively the tiniest babies at highest risk. SUMMARY: Avoidance, prevention, and treatment of inflammation to reduce this burden remain a major goal for neonatologists worldwide. In this review, we discuss the link between the host response to inflammatory stimuli and the disease state. We argue that inflammatory exposures play a key role in the pathobiology of preterm birth and that preterm neonates hereafter are highly susceptible to immune stimulation not only from their surrounding environment but also from therapeutic interventions employed in clinical care. Using bronchopulmonary dysplasia as an example, we report clinical studies demonstrating the potential utility of targeting inflammation to prevent this neonatal morbidity. On the contrary, we highlight limitations in our current understanding of how inflammation contributes to disease prevention and treatment. KEY MESSAGE: To be successful in preventing and treating inflammation-driven morbidity in neonatal intensive care, it may be necessary to better identify at-risk patients and pair therapeutic interventions to key pathways and mediators of inflammation-associated neonatal morbidity identified in pre-clinical and translational studies.