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Unrecognized transmission of pathogens in healthcare settings can lead to colonization and infection of both patients and healthcare personnel. The use of personal protective equipment (PPE) is an important strategy to protect healthcare personnel from contamination and to prevent the spread of pathogens to subsequent patients. However, optimal PPE use is difficult, and healthcare personnel may alter delivery of care because of the PPE. Here, we summarize recent research from the Prevention Epicenters Program on healthcare personnel contamination and improvement of the routine use of PPE as well as Ebola-specific PPE. Future efforts to optimize the use of PPE should include increasing adherence to protocols for PPE use, improving PPE design, and further research into the risks, benefits, and best practices of PPE use.