The global population is aging. With the high prevalence of dementia and functional decline in older Americans, many aging adults with disabilities reside in nursing homes in their final stage of life. Immunosenescence, multiple comorbid diseases, and grouped quarter living all coalesce in nursing home residents to increase the risk for infectious disease. The unique issues involved with diagnosis, prognosis, and management of infectious diseases in nursing home residents make research based in the nursing home setting both necessary and exciting for the physician investigator. This review discusses the opportunities and challenges involved with research of the evolving public health problem of infections among nursing home residents.