Infants in the neonatal intensive care unit are highly susceptible to healthcare associated infections (HAI), with a substantial impact on mortality, morbidity and healthcare costs. Effective skin disinfection with topical antiseptic agents is an important intervention in the prevention or reduction of HAI. A wide array of antiseptic preparations in varying concentrations and combinations has been used in neonatal units worldwide. In this article we have reviewed the current evidence of a preferred antiseptic of choice over other agents for topical skin disinfection in neonates. Chlorhexidine (CHG) appears to be a promising antiseptic agent; however there exists a significant concern regarding the safety of all agents used including CHG especially in preterm and very low birth weight infants. There is substantial evidence to support the use of CHG for umbilical cord cleansing and some evidence to support the use of topical emollients in reducing the mortality in infants born in developing countries. Well-designed large multicentre randomized clinical trials are urgently needed to guide us on the most appropriate and safe antiseptic to use in neonates undergoing intensive care, especially preterm infants.