Vaccination is one of the most effective methods used for protecting the public against infectious disease. Vaccines can be segregated into two general categories: replicating vaccines (i.e., live, attenuated vaccines) and non-replicating vaccines (e.g., inactivated or subunit vaccines). It has been assumed that live attenuated vaccines are superior to non-replicating vaccines in terms of the quality of the antiviral immune response, the level of protective immunity, and the duration of protective immunity. Although this a prevalent viewpoint within the field, there are several exceptions to the rule. Here, we will explore the historical literature in which some of these conclusions have been based, including "Experiments of Nature" and describe examples of the efficacy of replicating vaccines compared to their non-replicating counterparts. By building a better understanding of how successful vaccines work, we hope to develop better "next-generation" vaccines as well as new vaccines against HIV--a pathogen of global importance for which no licensed vaccine currently exists.