The arrival of COVID-19 vaccines that are highly effective against infection and severe disease in late 2020 appeared to be the silver bullet that would end the pandemic and bring life back to the way it was in pre-pandemic times. But the emergence of the highly infectious Delta variant of the virus, coupled with large portions of the eligible public remaining unvaccinated, has dampened much of this initial hope and led to what is being called the Fourth Wave of the pandemic. The surge in infections and hospitalizations in this latest wave is primarily in the unvaccinated; however, many vaccinated persons are experiencing “breakthrough infections” in which the virus evades the protection afforded by the vaccine. How can we interpret what these breakthrough infections mean regarding the effectiveness of the vaccine and the need for continuation of masking and other behaviors? In this episode, we aim to provide tools to prepare you to interpret the many reports on breakthrough infections encountered on the news and other media. Host Bryan James talks to Justin Lessler, now a professor of epidemiology at the University of North Carolina Gillings School of Global Public Health, and Lucy D’Agostino McGowan, assistant professor of statistics at Wake Forest University, about breakthrough COVID-19 infections and the Delta variant. They also talk about unvaccinated kids returning to school amongst all of this and the potential for booster shots.