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Biomarkers of infection, namely C-reactive protein and procalcitonin (PCT), are potentially useful in the diagnosis of infection as well as in the assessment of its response to antibiotic therapy. C-reactive protein variations overtime appears to have a good performance for the diagnosis of infection. Procalcitonin shows a better correlation with clinical severity. In addition, to overcome the worldwide problem of antibiotic overuse as well as misuse, biomarker guidance of antibiotic stewardship represents a promising new approach. In several randomized, controlled trials, including adult critically ill patients, PCT guidance was repeatedly associated with a decrease in the duration of antibiotic therapy. However, these trials present several limitations, namely high rate of patients’ exclusion, high rate of algorithm overruling, long duration of antibiotic therapy in the control group, disregard the effect of renal failure on PCT level, and above all a possible higher mortality and higher late organ failure in the PCT arm. In addition, some infections (e.g., endocarditis) as well as frequent nosocomial bacteria (e.g., Pseudomonas aeruginosa) are not suitable to be assessed by PCT algorithms. Therefore, the true value of PCT-guided algorithm of antibiotic stewardship in assisting the clinical decision-making process at the bedside remains uncertain. Future studies should take into account the issues identified in the present review.