Peripherally inserted central catheters (PICC lines) provide prolonged venous access, a means of administration of needed medications that would otherwise be irritating to peripheral vessels, and a means of assuring better parenteral nutrition to infants who are unable to tolerate enteral feedings. Not only do these central lines provide life-saving therapy, they are easily inserted, cost effective, and convenient. Although there are many benefits to the use of these catheters, physicians and nurses within the NICU must remain acutely aware of the risks involved with placement of PICC lines so that complications can be minimized. Prevention of sepsis in neonates is always a priority, and several measures can be implemented to reduce this risk, including scrupulous aseptic technique, knowledgeable selection of the insertion site, and consistent daily care. Other complications such as thrombosis, extravascular collection of fluid due to catheter migration or blockage, vessel perforation, and line leakage are all concerns when using this valuable tool in the care of infants. Careful catheter tip placement and conscientious ongoing monitoring can assist in reducing morbidity as well as mortality related to PICC lines.