Certain types of vaginal bacteria rapidly degrade a medication used to prevent HIV, a study of South African women reveals. The results help to explain why this particular drug has had disappointing efficacy in women. Today, high HIV acquisition rates among women are a major global health concern. While the microbicide drug tenofovir routinely prevents the virus in men at great risk, efficacy of this drug in females has been variable. To explore a role for the microbiome in this variability, Nichole Klatt and colleagues used samples collected from a subset of participants in a clinical trial evaluating the effectiveness of tenofovir intravaginal gel in preventing HIV in South African women; unfortunately, during the study period, some of these women went on to contract the virus. Among the samples they analyzed, Klatt et al. identified two major vaginal bacterial compositions in women - one dominated by the bacteria Lactobacillus, and the other, by Gardnerella vaginalis. Klatt et al. found that individuals where Lactobacillus predominated had around 3-fold greater protection against HIV acquisition, compared to those with non-Lactobacillus vaginal compositions. High HIV acquisition was found amongst those individuals where Gardnerella vaginalis dominated, because the bacteria could rapidly metabolize and breakdown the active form of the drug. These findings could have implications for which patients are administered the drug in the clinic, and for the design of public health programs and clinical trials. In a related Perspective, Susan Tuddenham and Khalil G. Ghanem note the study serves as a reminder that "without a deeper understanding of the structure, function, and dynamics of the vaginal microbiome, successful interventions to optimize it and improve women's health will remain elusive."