Childhood immunization constitutes one of the great success stories of American public health in the 20th century. This essay provides a historical examination of this topic through 4 particularly important examples: diphtheria, pertussis, polio, and measles. Each case study illustrates how new vaccines have posed unique challenges related to basic science, clinical trial methodology, medical ethics, and public acceptance. A brief comparison of each story to the experience of Great Britain, however, suggests an underlying unity connecting all 4 examples. Whereas the British led the way in introducing formal clinical trial methodology in the field of immunization development, the Americans excelled in the rapid translation of laboratory knowledge into strategies suitable for mass application. Although this distinction appears to have diminished in recent years, it offers insight into the sources of creativity underlying American vaccine development and the corresponding difficulties sometimes created for utilizing vaccines fruits rationally.