Purpose of Review <p>Machine perfusion strategies reduce the duration of organ ischemia and minimize tissue damage, increasing use of organs previously considered unsuitable for transplant. This review outlines the basic principles of organ preservation and machine perfusion, describes the risk of microbial contamination and role of antimicrobials during machine-based preservation, and discussed opportunities to leverage machine perfusion to reduce the risk of disease transmission.</p> Recent Findings <p>Ex situ machine perfusion (ESMP), which involves circulating perfusate through an organ’s vasculature to maintain physiological function, introduces new infectious considerations tied to its inherent function and real-world applications. Antimicrobials are routinely added to the perfusate in normothermic machine perfusion to mitigate the risk of microbial growth at normothermia. Microbial growth in ESMP perfusate has been described, but cultures often contain low-virulence organisms that do not predict post-transplant infection. Manipulation of organs on ESMP has been evaluated as a method to reduce the risk of infection transmission, but ESMP is not currently used for this purpose.</p> Summary <p>Current data do not suggest that ESMP systems confer a clinically significant infection risk over traditional preservation methods, but large, multicenter, prospective studies are needed to better understand infection risk. Universal treatment of recipients with antimicrobials targeting preservation fluid cultures is likely to be unnecessary, but the benefits of targeted treatment of certain potential pathogens could outweigh the risks. ESMP offers a potential platform for targeting donor-derived pathogens, but optimization of ex situ manipulation will be required for it to be an effective infection prevention approach.</p>