Procalcitonin (PCT) is useful for differentiating between viral and bacterial infections and for reducing the unnecessary use of antibiotics. As the rise of antimicrobial resistance reaches “alarming” levels according to the World Health Organization, the importance of using biomarkers, such as PCT to limit unnecessary antibiotic exposure has further increased. Randomized trials in patients with respiratory tract infections have shown that PCT has prognostic implications and its use, embedded in stewardship protocols, leads to reductions in the use of antibiotics in different clinical settings without compromising clinical outcomes. However, available data are heterogeneous and recent trials found no significant benefit. Still, from these trials, we have learned several key considerations for the optimal use of PCT, which depend on the clinical setting, severity of presentation, and pretest probability for bacterial infection. For patients with respiratory infections and sepsis, PCT can be used to determine whether to initiate antimicrobial therapy in low-risk settings and, together with clinical data, whether to discontinue antimicrobial therapy in certain high-risk settings. There is also increasing evidence regarding PCT-guided therapy in patients with coronavirus disease 2019 (COVID-19). This review provides an up-to-date overview of the use of PCT in different clinical settings and diseases, including a discussion about its potential to improve the care of patients with COVID-19.