Immunization has saved an estimated 154 million lives over the past 50 years since the launch of the Essential (formerly Expanded) Program on Immunization in 1974, representing 6 lives saved every minute, every year, for 50 years. But achieving and maintaining high immunization coverage have required sustained political and public commitment, financial resources, strong partnerships, research and innovation, and communication and advocacy. New and evolving challenges to maintaining high immunization coverage have emerged alongside long-standing stubborn obstacles. We review some of these key challenges to immunization in this dynamic, changing world and summarize some promising solutions. Success in some regions of the world in eliminating polio, measles, and rubella, and reducing morbidity and mortality from other vaccine-preventable diseases (VPDs), should provide hope that progress can be made in achieving and maintaining high immunization coverage. We cannot afford to do otherwise.