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Whilst many guidelines recommend limiting the use of antibiotics because of the increase in antimicrobial resistance (AMR), this strategy becomes challenging when dealing with severe infections in critically ill patients. Moreover, some Gram-negative bacilli (GNB) can exhibit mechanisms of resistance that make the patient more vulnerable to recurrence of infections. We reviewed recent data on the optimal duration of antibiotic therapy in these patients.Apart from having no additional clinical benefit at a certain point after initiation, antibiotics might have negative effects. Prolonged antibiotic exposure has been associated to development of AMR and represents a strong reason to avoid long courses of antibiotic therapy in GNB infections. Recent data suggest that also patients with severe infections, in whom source control is adequate, can be managed with short-course antibiotic therapy.The optimal duration of antibiotic therapy depends on many factors, but overall, many infections in the critically ill can be treated with short-course antibiotic therapy (7 days or less). The integration of signs of resolution, biomarkers, clinical judgment, and microbiologic eradication might help to define this optimal duration in patients with life-threatening infections caused by GNB.