Opinions are divided regarding the management of a persistently patent ductus arteriosus (PDA). Some of the adverse effects associated with a large hemodynamically significant duct, including prolonged ventilation, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and mortality, indicate that active management of infants with large ductal shunts may sometimes be necessary. Indomethacin and ibuprofen are the two US FDA-approved cyclooxygenase (COX) inhibitors used for the closure of a ductus in preterm babies. Both these drugs are effective in 70-80% of extremely low birthweight infants. Treatment with COX inhibitors may be associated with renal impairment, gastrointestinal hemorrhage, NEC, and spontaneous intestinal perforation when given concurrently with steroids, as well as changes in cerebrovascular auto-regulation. Ibuprofen appears to be a better choice for PDA closure, with a better side effect profile and efficacy that equals that of indomethacin. However, long-term outcome studies of ibuprofen are lacking, and prophylactic ibuprofen is ineffective in decreasing severe IVH. The choice of one drug over the other also depends on local availability of both drugs and the intravenous or enteral preparation. The oral preparation of ibuprofen appears as effective as the intravenous preparation. The use of paracetamol to close a hemodynamically significant PDA has increased in recent years. Paracetamol also decreases prostacyclin synthesis; however, unlike COX inhibitors, it does not have a peripheral vaso-constrictive effect and can be given to infants with contraindications to non-steroidal anti-inflammatory drugs. It appears to have similar efficacy based on limited data available from randomized trials. Until more data are available on efficacy, safety, and long-term outcomes, it cannot be recommended as the first choice.