Systemic hypotension during the first postnatal week is associated with increased mortality and morbidity in the very low birth weight (VLBW) neonate. Hypotension is generally defined as blood pressure below the fifth percentile of the gestational- and postnatal-age dependent blood pressure norms. Recent studies indicate that in most VLBW neonates, cerebral blood flow autoregulation is indeed lost when blood pressure reaches the fifth percentile. Treatment of the circulatory compromise should address the primary pathogenic factor(s) of the condition (hypovolemia, myocardial compromise, failure of vasoregulation or a combination of factors). Recent findings also suggest that vasopressor resistance can be treated with a brief course of low-dose hydrocortisone. However, due to the short- and potential long-term side effects of early hydrocortisone treatment, its use should be restricted to neonates with vasopressor-resistant hypotension. Finally, concomitant administration of hydrocortisone with indomethacin should be avoided due to the increased incidence of gastrointestinal perforations.