Rational vaccine design remains a long sought and ambitious goal. While animal studies have been extremely important to unravel the fundamental mechanisms that govern the immune response, we are still facing the challenge of understanding the human immune system in its complexity and genetic heterogeneity and in unraveling the sophisticated escape mechanism used by human pathogens. In spite of obvious limitations in human experimentations and clinical trial, the twenty first century vaccinologists can take advantage of new tools and experimental approaches to identify the mechanisms of protection as well as the antigens that are target of protective responses. The formulation of these antigens together with new adjuvants capable of eliciting strong and durable immune responses of the appropriate class will be the basis for the design of a panoply of vaccines that will be able to deal effectively with a variety of threats to human health.