Differentiating between inflammatory disorders is difficult, but important for a rational use of antimicrobial agents. Biomarkers reflecting the host immune response may offer an attractive strategy to predict the etiology of an inflammatory process and can thus be of help in decision making. We performed a review of the literature to evaluate the diagnostic value of inflammatory biomarkers in adult patients admitted to the hospital with suspected systemic acute infections. Elevated procalcitonin (PCT) concentrations indicate a bacterial infection in febrile patients with an auto-immune disease, rather than a disease flare. CD64 expression on neutrophils can discriminate between non-infectious systemic inflammation and sepsis, and limited evidence suggests the same for decoy receptor 3. PCT is useful for both diagnosing bacterial infection complicating influenza and guiding antibiotic treatment in lower respiratory tract infections in general. In undifferentiated illnesses, increased CD35 expression on neutrophils distinguishes bacterial from viral infections. Compared to bacterial infections, invasive fungal infections are characterized by low concentrations of PCT. No biomarker predicting a specific infecting agent could be identified.