The development and widespread use, in the United States and globally, of safe and effective vaccines has been one of the greatest achievements in science, medicine, and public health—saving lives, preventing disabilities, contributing to improvements in life expectancy, and reducing health care costs. Serious and once common childhood infections are increasingly joining the ranks of “vaccine-preventable diseases.” The number of childhood and adolescent diseases prevented by vaccines has increased from 10 to 16 in just the last 10 years. Moreover, we now have vaccines that can prevent the infections that can lead to cervical and liver cancer. Ironically, as the threat of disease has been diminished by vaccines, there has been increasing attention on the risks, both real and perceived, from vaccines. When vaccines are used effectively, the incidence of vaccine-preventable diseases declines, and over time, the diseases that vaccines have prevented are less common. The result is that there is a subtle shift in the benefit/risk ratio. With the recent addition of new vaccines to the recommended childhood immunization schedule, an increasing number of parents have raised concerns that their children are receiving more vaccines than they need. Changes in information technology, such as the Internet, provide more access to information, both accurate and inaccurate. The safety standards for vaccines are arguably higher than those of any other medical product because vaccines are given to healthy persons to prevent disease, are recommended for near-universal use, and are often required by state laws for school entrance. Nevertheless, no medical product, including vaccines, is risk free. Similar to other infrastructures, the components of the US vaccine-safety system may not be familiar to many people. Because the quality and transparency of this system are critical to maintaining public confidence in our immunization program, this supplement to Pediatrics has been assembled to help … Address correspondence to Daniel Salmon, PhD, MPH, National Vaccine Program Office, Office of Public Health and Science, Office of the Secretary, Department of Health and Human Services, 200 Independence Ave SW, Room 715H, Washington, DC 20201. E-mail: daniel.salmon{at}hhs.gov