Just as the world appeared to be winning the battle against COVID-19, the rules of the game changed. Omicron and concerns about future variants flipped the board. Vaccines and monoclonal antibodies are attracting fresh scrutiny as SARS-CoV-2 evolves. Cases are climbing closer to the highest levels recorded since the pandemic began. Antivirals are aiming to fill treatment gaps, but whether they will or not is about as clear as the virus’ next move.