Many newborns are exposed to diagnostic or treatment procedures due to a suspicion of sepsis. Since non-specific signs of neonatal sepsis can quickly proceed to a life-threatening condition, it is essential to have a low threshold to diagnostic procedures and to provide antimicrobial therapy while waiting for the test results. After sepsis has been ruled out, antimicrobial therapy should be discontinued without delay. Good clinical practice includes avoiding unnecessarily broad-spectrum antibiotics. The future challenge is to develop a sensitive and specific marker for early detection of the disease and for avoiding unnecessary antibiotics, hospital care days and mother-infant separation.