Adolescents with chronic medical conditions (CMCs), a growing population worldwide, possess a wide array of preventive health care needs. Vaccination is strongly recommended for the vast majority of these adolescents given their increased risk of vaccine preventable infection and associated complications. Not only should they receive routine vaccines, but some also require additional vaccines. Despite these guidelines, evidence suggests that adolescents with CMCs often fail to receive needed vaccines. Many factors contribute to this under-immunization, including lack of knowledge among parents and providers and suboptimal coordination of primary and subspecialty care. This review describes current vaccination recommendations for these adolescents as well as recent data related to infection risk, vaccine efficacy and safety, vaccination coverage, and the unique multilevel factors impacting uptake in this population. It also discusses strategies for improving coverage levels and reducing missed vaccination opportunities, with a particular focus on technology-based interventions.