The use of biomarkers provides a novel approach to diagnosing infection, its severity and treatment response. Biomarkers, especially procalcitonin and, to a lesser extent, C-reactive protein and interleukin 8, can improve the diagnostic and prognostic assessment of bloodstream infections. Both strengths and weaknesses of biomarkers must be recognized for rational and safe use in clinical settings. Cut-off ranges must be chosen within the specific clinical context. Ultrasensitive assays for procalcitonin, capable of measuring low levels in healthy individuals, may help to identify even 'subclinical' inflammatory states before the development of clinically evident sepsis. For immunocompromised patients, the use of biomarkers could lead to an earlier and more targeted antimicrobial therapy for patients at risk of sepsis, whereas those patients with viral illness or a non-infectious aetiology of inflammation who maintain low levels of procalcitonin over time can be withheld from antibiotic exposure. The time has arrived to move beyond the observational reporting of 'promising' biomarkers. Specific cut-off ranges must be proposed and intervention studies conducted to tackle the existing vicious cycle of diagnostic uncertainty, antibiotic overuse and emerging multi-resistance.