Although standard respiratory care as following a universal protocol is usually adequate for the majority of hospitalised newborn infants with acute or chronic respiratory pathology, clinical management can be particularly challenging in some critical extremes. This difficulty can clinically translate to unsuccessful weaning off invasive support or even decreased survival. Such critical conditions are extreme prematurity below 24 completed weeks of gestation or marked lung hypoplasia second to severe antenatal diseases and conditions such as congenital diaphragmatic hernia or premature prolonged rupture of membranes. Another crucial clinical threshold in neonatal intensive care is defined by the ability of premature infants to extubate successfully—to wean off invasive mechanical ventilation and to be able to sustain independent breathing. Life in high altitude is synonymous to prolonged exposure to baseline hypoxia and can also negatively affect intrauterine development and postnatal respiratory health. These critical extremes offer valuable insight in the respiratory pathophysiology of the newborn and the effect of chronic conditions on acute and chronic respiratory outcomes.