This review aims to summarize current progress in the management of critically ill, using biomarkers as guidance for antimicrobial treatment with a focus on antimicrobial stewardship. Accumulated evidence from randomized clinical trials (RCTs) and observational studies in adults for the biomarker-guided antimicrobial treatment of critically ill (mainly sepsis and COVID-19 patients) has been extensively searched and is provided. Procalcitonin (PCT) is the best studied biomarker; in the majority of randomized clinical trials an algorithm of discontinuation of antibiotics with decreasing PCT over serial measurements has been proven safe and effective to reduce length of antimicrobial treatment, antibiotic-associated adverse events and long-term infectious complications like infections by multidrug-resistant organisms and Clostridioides difficile. Other biomarkers, such as C-reactive protein and presepsin, are already being tested as guidance for shorter antimicrobial treatment, but more research is needed. Current evidence suggests that biomarkers, mainly procalcitonin, should be implemented in antimicrobial stewardship programs even in the COVID-19 era, when, although bacterial coinfection rate is low, antimicrobial overconsumption remains high.