Traditionally, studies investigating the usefulness of a biomarker focus on diagnostic measures such as sensitivity and specificity. This approach, however, mandates the existence of a well-accepted reference standard. For biomarkers that are used to help treat patients with systemic infections and sepsis there is no such reference standard, with blood cultures having low sensitivity of only 10% to 30%. Thus, randomized controlled trials are needed to assess the benefits and limitations of infection biomarkers by comparing outcomes of marker-assessed patients with patients receiving routine care. In the case of procalcitonin (PCT) and its effect in the treatment of patients with sepsis, numerous studies have investigated how well this marker differentiates patients with true sepsis from patients presenting with a sepsis-like syndrome but no infectious etiology. Depending on the cutoff used, reported sensitivities and specificities range between 70% and 95%, with the lack of a reference standard making the interpretation of these results challenging. Importantly, several randomized trials have investigated the effects of PCT protocols and report important reductions in antibiotic use in the range of 30% to 70%, depending on the clinical setting and main infection diagnosis,, with a recent trial finding a significant survival benefit associated with the use of PCT in the critical care setting.