Purpose of reviewPulmonary infections due to Gram-negative organisms are increasing worldwide and traditional assumptions that these are limited to hospital and ventilator-acquired pneumonia are rapidly falling away. Accordingly, empiric antibiotic guidelines have to follow suit with ever broader spectrum choices in order to remain ‘safe’, as the Global prevalence of extensively resistant Gram-negative organisms inexorably increases. Rapid, multiplex PCR-based detection of a wide variety of potential pathogens offers the opportunity to replace empiric antibiotic choices with targeted, evidence-based therapy in clinically actionable timeframes.Recent findingsHere, we describe the data underpinning both the increasing global prevalence of Gram-negative pulmonary infections and their increasing antibiotic resistance. We also describe the performance, characteristics and early emerging clinical impact of already available rapid molecular diagnostic platforms and how they might best be deployed.SummaryIt will likely be advantageous to replace the current trend for empiric prescription of increasingly broad-spectrum antibiotics with ‘same day’ evidence-based, targeted therapy using high performance, rapid molecular diagnostic solutions. Several challenges remain be overcome, however, to fully realize their clear potential for better, focussed deployment of antibiotics, improved patient outcomes and antibiotic stewardship.