Antibiotics can improve the prognosis in patients with exacerbation of chronic obstructive pulmonary disease. However, the overuse of antibiotics can carry serious adverse effects for patients (gastrointestinal infections) and for society (bacterial resistance). Likewise, systemic corticosteroids may also help these patients, but also carries severe adverse effects like osteoporosis, muscle loss, and diabetes, in many patients. Whenever safe methods exist to reduce these two treatment modalities, they should be implemented. The blood biomarkers procalcitonin and the fraction of leukocytes known as eosinophil granulocytes have been proven in randomized controlled trials (RCTs), to effectively, significantly, and substantially assist in reducing the use of these two potent, yet toxic medication types. In this review, the background and main clinical results are discussed, explaining the rationale for biomarker-guided clinical decisions. Also, the main expected effects, their sizes, and importantly the limitations to such a strategy are described. Clinical evidence is prioritized with main weight on RCTs and meta-analyses of these and regarding outcomes, and focus is set on the safety of such a biomarker-guided strategy, as well as the effects on medicine reduction. In an epoch of increasing demands to physicians from patients and politicians to cure and reduce symptoms, the Hippocratic phrase of "primum non nocere"or "first, do no harm"seems more than ever of contemporary importance.