The growing success of solid organ transplantation poses unique challenges for the implementation of effective immunization strategies. Although live attenuated vaccines have proven benefits for the general population, immunosuppressed patients are at risk for unique complications such as infection from the vaccine because of lack of both clearance and containment of a live attenuated virus. Moreover, while vaccination strategies using killed organisms or purified peptides are believed to be safe for immunosuppressed patients, they may have reduced efficacy in this population. The current lack of knowledge of the basic safety and efficacy of vaccination strategies in the immunosuppressed has limited the development of guidelines regarding vaccination in this population. Recent fears of influenza pandemics and potential attacks by weaponized pathogens such as smallpox heighten the need for increased knowledge. Herein, we review the current understanding of the effects of immunosuppressants on the immune system and the ability of the suppressed immune system to respond to vaccination. This review highlights the need for systematic, longitudinal studies in both humans and nonhuman primates to understand better the defects in innate and adaptive immunity in transplant recipients, thereby aiding the development of strategies to vaccinate these individuals.