Vaccines have had a profound influence on human health with no other health intervention rivaling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variation in the genome and transcriptome to immunological measures of vaccine responsiveness. These approaches have provided fresh insight into the intrinsic factors determining the potency and duration of vaccine-induced immunity. The fundamental challenge will be to translate these findings into innovative and pragmatic strategies to develop new and more effective vaccines.