Background <p>While advancements in neonatal intensive care have significantly improved the survival of preterm infants, inflammation-related complications continue to be a major factor in short- and long-term morbidity, especially in the most immature babies. Profound evidence indicates that prenatal and postnatal inflammatory exposures, interacting in a multi-hit sequence, significantly affect both immune responses and long-term organ development.</p> Content <p>While preterm birth frequently represents the initial trigger of an adverse cascade of inflammation, various postnatal environmental factors, such as respiratory support, oxygen therapy, and neonatal infections, contribute to this process, with each event serving as an inflammatory stressor independently associating with inflammation-driven tissue damage. The preterm innate immune system seems particularly susceptible not only to infection, but to pro-inflammatory immune responses and sustained immune activation. Mechanistically, several processes have been implicated, including disturbed homeostasis of inflammatory mediators, antioxidant enzymes, and proteases, as well as altered pathogen recognition, and particularities in the resolution of inflammation. In addition, trained immunity, immune tolerance, epigenetic and metabolic reprogramming, and interactions between altered gut microbiota and the developing immune system may further shape these responses. Subsequently altered, often increased or sustained inflammation has been recognized as a central mechanism linking early-life exposures to impaired lung, brain, gut, and retinal development, and adverse long-term outcomes. The frequency of episodes of inflammation seems to significantly impact the latter.</p> Conclusions <p>A better understanding and greater awareness may enable improved risk stratification and avoidance of inflammatory exposures, and promote the development of more targeted strategies to prevent adverse inflammation during a vulnerable period.</p>