Due to overlap of clinical findings and low sensitivity of bacterial diagnostic tests, differentiation between bacterial and viral respiratory tract infections remains challenging, ultimately leading to antibiotic overuse in this population of patients. Addition of procalcitonin, a blood biomarker expressed by epithelial cells in response to bacterial infections, to the clinical assessment leads to a reduction in inappropriate antibiotic initiation. Procalcitonin also provides prognostic information about the resolution of illness, and significant decreases over time are a strong signal for the discontinuation of antibiotics. Current evidence from randomized trials indicates that procalcitonin-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side effects, which importantly translates into improved survival of patients with respiratory infections. Inclusion of procalcitonin into antibiotic stewardship algorithms thus improves the diagnostic and therapeutic management of patients presenting with respiratory illnesses and holds great promise to mitigate the global bacterial resistance crisis.