Vaccine hesitancy (VH) represents a major global public health threat, undermining efforts to control infectious diseases and jeopardizing the success of immunization programs. While traditionally associated with childhood vaccination, VH is increasingly relevant among adults and older adults, where uptake of influenza, pneumococcal, herpes zoster, COVID-19, and respiratory syncytial virus (RSV) vaccines remains suboptimal. This chapter examines the multifaceted determinants of VH in these populations, including psychological, sociocultural, and organizational factors, and their interplay in shaping vaccine decisions. It highlights the disproportionate disease burden in the elderly, the importance of a lifelong vaccination calendar as endorsed by the WHO Immunization Agenda 2030, and the persistent gaps in coverage due to low awareness, misinformation, and accessibility barriers. Lessons learned from the COVID-19 pandemic underscore the influence of rapid vaccine development, politicization, inequities, and the “infodemic” on public trust, while also revealing opportunities for innovation in vaccine delivery and communication. Particular emphasis is placed on the pivotal role of healthcare workers as trusted sources of information and facilitators of access, as well as on organizational strategies—such as multicomponent interventions, reminder systems, home visits, and service integration—that can counteract VH. Ultimately, addressing VH among adults and the elderly requires culturally sensitive communication, systemic organizational change, and the integration of vaccination into the broader framework of preventive care and healthy ageing.