SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers-individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease-present a unique opportunity to reveal human genetic determinants of infection and disease. To understand the genetic requirements for immune control of SARS-CoV-2, in February 2020, we began recruiting COVID-19 patients from as many centers and countries as possible to the COVID Human Genetic Effort. The exome and genome data are analyzed simultaneously locally at the hubs and centrally by the consortium. Hypotheses of genetic heterogeneity (one causal locus per kindred) and genetic homogeneity (a causal locus in two or more kindreds) are being tested in parallel. The large number of patients may facilitate the detection of promising candidate genotypes in single patients or families, including variants of known viral susceptibility genes.