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Over the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the clinical, scientific, and public health communities have had to respond to new viral genetic variants. Each one has triggered a flurry of media attention, a range of reactions from the scientific community, and calls from governments to either “stay calm” or pursue immediate countermeasures. While many scientists were initially skeptical about the significance of the D614G alteration, the emergence of the new “UK variant”—lineage B.1.1.7—has raised widespread concern. Understanding which variants are concerning, and why, requires an appreciation of virus evolution and the genomic epidemiology of SARS-CoV-2.