Vaccines save millions of lives every year. They are one of the safest and most effective public health interventions in keeping populations healthy while bringing numerous social and economic benefits. Vaccines play an important role in ensuring that children, regardless of where they live, can have a healthy start to life. New financing mechanisms that allow poorer countries to gain access to vaccines faster than ever mean additional deaths and disabilities are projected to be saved during the Decade of Vaccines (2011–2020). Trust in vaccines and in the health system is an important element of public health programs that aim to deliver life-saving vaccines. Indeed, understanding the contributors and threats to trust is essential to explaining vaccine acceptance, particularly as they vary across epidemiologic conditions, specific vaccines and cultural and sociopolitical settings. Greater efforts to communicate the benefits and risks of vaccines and address issues with evidence-based information will help improve and sustain public trust in vaccines and health systems worldwide. Measuring and monitoring trust levels and focusing on deliberate efforts to build trust in vaccines are important steps to reducing vaccine confidence gaps when they occur.