The review assesses the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, details the S protein adaptations that facilitate efficient human transmission, and examines the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. The review was authored by Cody B. Jackson, Michael Farzan, and Hyeryun Choe of Scripps Research, in collaboration with Bing Chen of Harvard Medical School. The issue also features a review of SARS-CoV-2 replication and transcription by Brandon Malone, Nadya Urakova, Eric J. Snijder, and Elizabeth A. Campbell.