COVID-19 is a zoonosis like most of the great plagues sculpting human history, from smallpox to pandemic influenza and human immunodeficiency virus. When viruses jump into a new species the outcome of infection ranges from asymptomatic to lethal, historically ascribed to “genetic resistance to viral disease”. People have exploited these differences for good and bad, for developing vaccines from cowpox and horsepox virus, controlling rabbit plagues with myxoma virus, and introducing smallpox during colonisation of America and Australia. Differences in resistance to viral disease are at the core of the SARS-CoV-2 crisis, yet our understanding of the mechanisms in any interspecies leap falls short of the mark. Here I review how the two key parameters of viral disease are countered by fundamentally different genetic mechanisms for resistance: 1. virus transmission, countered primarily by activation of innate and adaptive immune responses; and 2. pathology, countered primarily by tolerance checkpoints to limit innate and adaptive immune responses. I discuss tolerance thresholds and the role of CD8 T cells to limit pathological immune responses, the problems posed by tolerant superspreaders, and the signature coronavirus evasion strategy of eliciting only short-lived neutralising antibody responses. Pinpointing and targeting the mechanisms responsible for varying pathology and short-lived antibody was beyond reach in previous zoonoses, but this time we are armed with genomic technologies and more knowledge of immune checkpoint genes. These known unknowns must now be tackled to solve the current COVID-19 crisis and the inevitable zoonoses to follow.This article is protected by copyright. All rights reserved.