Vaccine hesitancy reflects concerns about the decision to vaccinate oneself or one's children. There is a broad range of factors contributing to vaccine hesitancy, including the compulsory nature of vaccines, their coincidental temporal relationships to adverse health outcomes, unfamiliarity with vaccine-preventable diseases, and lack of trust in corporations and public health agencies. Although vaccination is a norm in the U.S. and the majority of parents vaccinate their children, many do so amid concerns. The proportion of parents claiming non-medical exemptions to school immunization requirements has been increasing over the past decade. Vaccine refusal has been associated with outbreaks of invasive Haemophilus influenzae type b disease, varicella, pneumococcal disease, measles, and pertussis, resulting in the unnecessary suffering of young children and waste of limited public health resources. Vaccine hesitancy is an extremely important issue that needs to be addressed because effective control of vaccine-preventable diseases generally requires indefinite maintenance of extremely high rates of timely vaccination. The multifactorial and complex causes of vaccine hesitancy require a broad range of approaches on the individual, provider, health system, and national levels. These include standardized measurement tools to quantify and locate clustering of vaccine hesitancy and better understand issues of trust; rapid, independent, and transparent review of an enhanced and appropriately funded vaccine safety system; adequate reimbursement for vaccine risk communication in doctors' offices; and individually tailored messages for parents who have vaccine concerns, especially first-time pregnant women. The potential of vaccines to prevent illness and save lives has never been greater. Yet, that potential is directly dependent on parental acceptance of vaccines, which requires confidence in vaccines, healthcare providers who recommend and administer vaccines, and the systems to make sure vaccines are safe.