The ability to test validity by replicating experiments and comparing results is a cornerstone of science. The events that followed publication of “Sustained virologic control in SIV + macaques after antiretroviral and α 4 β 7 antibody therapy” by Byrareddy et al. in Science in 2016 (hereafter Byrareddy) provide insights into some challenges associated with replication. Byrareddy reported striking efficacy of an approach for controlling simian immunodeficiency virus (SIV) in rhesus macaques in a sustained manner, a result of potential importance for treatment of human HIV disease. Three papers in this issue report attempts to replicate these results. The matters associated with Byrareddy and these studies provide a concrete framework for discussing our policies related to replication studies.