Several biochemical markers have been proposed over the past years to manage critically ill newborns with acute inflammation and sepsis. The state of the art in diagnosing and monitoring neonatal sepsis, severe sepsis and septic shock consists of the measurement of plasma C-reactive protein (CRP) and procalcitonin (PCT) at the onset and in the course of the disease. CRP and PCT in combination are clinically significant in diagnosing and monitoring septic newborns; however, CRP and PCT have a very limited value for risk stratification and in predicting outcome. The availability of commercial methods for the automated measurement of the soluble CD14 subtype presepsin (sCD14-ST) and lipopolysaccharide binding protein (LBP) represent a challenge for the evaluation in clinical practice of reliable markers of neonatal sepsis, specifically for the very early diagnosis, the classification into class of severity, and the prediction of complications and death.