Protecting vulnerable populations from pandemic influenza is a strategic imperative. The US national strategy for pandemic influenza preparedness and response assigns roles to governments, businesses, civic and community-based organizations, individuals, and families. Because influenza is highly contagious, inadequate preparedness or untimely response in vulnerable populations increases the risk of infection for the general population. Recent public health emergencies have reinforced the importance of preparedness and the challenges of effective response among vulnerable populations. We explore definitions and determinants of vulnerable, at-risk, and special populations and highlight approaches for ensuring that pandemic influenza preparedness includes these populations and enables them to respond appropriately. We also provide an overview of population-specific and cross-cutting articles in this theme issue on influenza preparedness for vulnerable populations.