The emergence and spread of extensively multidrug-resistant organisms is a public health crisis, and long-term care settings have been identified as a reservoir for the cultivation of these organisms. Long-term care settings are now taking on increasingly ill residents with complicated medical problems, indwelling devices, and significant healthcare exposure, all of which are considered risk factors selecting for resistant organisms. Despite this, guidelines addressing infection prevention procedures in long-term care remain vague, and implementation of these guidelines is challenging, largely due to staff turnover, limited resources, knowledge gaps, and lack of organizational support. Human factors engineering approaches have emerged as an important innovation to address patient safety issues and develop interventions in the healthcare work system (ie, tools and technologies, tasks, organization, physical environment) that support human performance, which, in turn, lead to improvements in processes (eg, compliance with infection prevention guidelines) and outcomes (eg, reduced infection rates). We propose the concept of using the methods and approaches from the scientific field of human factors engineering to address the unique challenges of implementing infection prevention in the long-term care setting.