Concerns about possible allergic reactions to immunizations are raised frequently by both patients/parents and primary care providers. Estimates of true allergic, or immediate hypersensitivity, reactions to routine vaccines range from 1 per 50000 doses for diphtheria-tetanus-pertussis to approximately 1 per 500000 to 1000000 doses for most other vaccines. In a large study from New Zealand, data were collected during a 5-year period on 15 marketed vaccines and revealed an estimated rate of 1 immediate hypersensitivity reaction per 450000 doses of vaccine administered. Another large study, conducted within the Vaccine Safety Datalink, described a range of reaction rates to >7.5 million doses. Depending on the study design and the time after the immunization event, reaction rates varied from 0.65 cases per million doses to 1.53 cases per million doses when additional allergy codes were included. For some vaccines, particularly when allergens such as gelatin are part of the formulation (eg, Japanese encephalitis), higher rates of serious allergic reactions may occur. Although these per-dose estimates suggest that true hypersensitivity reactions are quite rare, the large number of doses that are administered, especially for the commonly used vaccines, makes this a relatively common clinical problem. In this review, we present background information on vaccine hypersensitivity, followed by a detailed algorithm that provides a rational and organized approach for the evaluation and treatment of patients with suspected hypersensitivity. We then include 3 cases of suspected allergic reactions to vaccines that have been referred to the Clinical Immunization Safety Assessment network to demonstrate the practical application of the algorithm.