Procalcitonin is a surrogate biomarker for estimating the likelihood of a bacterial infection. Procalcitonin-guided initiation and termination of antibiotic therapy is a novel approach utilized to reduce antibiotic overuse. This is essential to decrease the risk of side effects and emerging bacterial multiresistance. Interpretation of procalcitonin levels must always comprise the clinical setting and knowledge about assay characteristics. Only highly sensitive procalcitonin assays should be used in clinical practice and cut-off ranges must be adapted to the disease and setting. Highly sensitive procalcitonin measurements, embedded in diagnosis-specific clinical algorithms, have been shown to markedly reduce the overuse of antibiotic therapy without increasing risk to patients in 11 randomized controlled trials including over 3500 patients from different European countries. In primary care and emergency department patients with mild and mostly viral respiratory infections (acute bronchitis), the initial prescription of antibiotics was reduced by 30-80%. In hospitalized and more severely ill patients with community-acquired pneumonia and sepsis, the main effect was a reduction of the duration of antibiotic courses by 25-65%. This review aims to provide physicians with an overview of the strengths and limitations of procalcitonin guidance for antibiotic therapy when used in different clinical settings and in patients with different underlying infections.