OBJECTIVE To review the current evidence on the use of infection markers for diagnostic evaluation of sepsis in neonates. RESULTS Recent research in immunology has led to the discovery of cell surface antigens, chemokines, cytokines and acute phase proteins that can potentially be used to 'rule in' or 'rule out' sepsis. The diagnostic utilities of key inflammatory mediators, including CD11b, CD64, interleukin-6 and interleukin-8, are promising and likely to become increasingly used as markers of infection for both diagnostic and prognostic purposes. CONCLUSIONS Serial measurements and use of combinations of markers have been reported to improve sensitivity and negative predictive value of these tests. Current markers are not infallible, however, and do not permit neonatologists to withhold antibiotics in sick infants with suspected infection. Thus, many have emerged as useful indicators for early discontinuation of unnecessary antimicrobial therapy. Some infection markers are also useful for identifying infants with severe infection and adverse prognosis. Advances in flow cytometry have allowed simultaneous measurement of key markers using only minimal blood volume. Judicious selection of a panel of markers with complementary properties could greatly increase the ability of neonatologists to diagnose infection and discern valuable prognostic information.