Vaccines against childhood diseases represent some of the most important applications of 20th-century pediatric research. This survey examines how the components of the current U.S. immunization schedule emerged in three phases during the course of the century. The first phase, after the development of bacterial culture techniques, witnessed numerous efforts in the early 1900s to develop bacterial vaccines. It proved most fruitful with respect to diphtheria, tetanus, and pertussis. The rise of viral tissue culture techniques in the 1950s brought about a second phase of innovation resulting in vaccines against polio, measles, mumps, rubella, and varicella. A third wave of innovation, still very much alive, has drawn on a variety of new technologies and led to vaccines against hepatitis B, Haemophilus influenzae type b, pneumococcus, and still other organisms. Although basic science research has thus been a primary factor shaping the history of vaccine development, the collaboration between the academic, private, and public sectors critical to its application has not always proceeded smoothly. The history of vaccine research and development has important implications for today, as a variety of factors threaten to fragment this network.