International efforts to eradicate smallpox in the 1960s and 1970s provided the foundation for efforts to expand immunization programmes, including work to develop immunization supply chains. The need to create a reliable system to keep vaccines cold during the lengthy journey from the manufacturer to the point of use, even in remote areas, was a crucial concern during the early days of the Expanded Programme on Immunization. The vaccine cold chain was deliberately separated from other medical distribution systems to assure timely access to and control of vaccines and injection materials. The story of the early development of the vaccine cold chain shows how a number of challenges were overcome with technological and human resource solutions. For example, the lack of methods to monitor exposure of vaccines to heat during transport and storage led to many innovations, including temperature-sensitive vaccine vial monitors and better methods to record and communicate temperatures in vaccine stores. The need for appropriate equipment to store and transport vaccines in tropical developing countries led to innovations in refrigeration equipment as well as the introduction and widespread adoption of novel high performance vaccine cold-boxes and carriers. New technologies also helped to make injection safer. Underlying this work on technologies and equipment was a major effort to develop the human resources required to manage and implement the immunization supply chain. This included creating foundational policies and a management infrastructure; providing training for managers, health workers, technicians, and others. The vaccine cold chain has contributed to one of the world’s public health success stories and provides three priority lessons for future: the vaccine supply chain needs to be integrated with other public health supplies, re-designed for efficiency and effectiveness and work is needed in the longer term to eliminate the need for refrigeration in the supply chain.