Diagnostic uncertainty (DU) is frequent in infectious diseases (ID), being recorded in 10% to over 50% of patients. Herein, we show that in several fields of clinical practice, high rates of DU are constant over time. DUs are not taken into account in guidelines, as therapeutic propositions are based on an established diagnosis. Moreover, while other guidelines underline the need for rapid broad-spectrum antibiotic therapy for patients with sepsis, many clinical conditions mimic sepsis and lead to unnecessary antibiotic therapy. Considering DU, many studies have been carried out to look for relevant biomarkers of infections, which also attest to non-infectious diseases mimicking infections. Therefore, diagnosis is often primarily a hypothesis, and empirical antibiotic therapy should be reassessed when microbiological data are available. However, other than for urinary tract infections or unexpected primary bacteremia, the high frequency of sterile microbiological samples implies that DU remains central in follow-up, which does not facilitate clinical management or antibiotic optimization. The main way to resolve the therapeutic challenge of DU could be to precisely describe the latter through a consensual definition that would facilitate consideration of DU and its mandatory therapeutic implications. A consensual definition of DU would also clarify responsibility and accountability for physicians in the antimicrobial approval process and l provide an opportunity to instruct their students in this large field of medical practices and to productively conduct relevant research.