The twentieth century saw multiple viruses that spread around the world causing misery and death. The 1917 influenza pandemic (Chap. 5 ) killed tens of millions of men, women, and children and spared no part of the world. In terms of sheer numbers of cases and deaths, influenza was the top viral killer of the century. Of all the viruses with lethal capability, influenza was considered the most likely culprit to cause another pandemic but that worry never materialized. Next came poliovirus that rose from obscurity, panicking parents, and spreading terror throughout the developed nations (Chap. 6 ). Its ability to kill and cripple defenseless children made it a horrific disease even if the number of actual deaths was much smaller than for influenza. And just as many dangerous viruses were being controlled through vaccination, the AIDS virus (human immunodeficiency virus—HIV) became a global scourge that is still not conquered (Chap. 15 ). HIV spread silently for many years until it exploded with a surge of cases in the 1980s, presenting in young men with bizarre and unusual infections, often from organisms that normally weren’t pathogens. As a sexually transmitted and blood-borne disease, HIV changed both social mores and medical practice as universal precautions and safe sex became a standard. Each of these viruses dramatically impacted both science and society, and any of them could lay claim to be the most important virus of the last century. The twenty-first century is still in its infancy, but we already have a strong frontrunner for the most impactful virus of this century, SARS-Coronavirus -2 (SARS-CoV-2).