Five years ago, we launched the COVID Human Genetic Effort. Our goal was to explain the clinical variability among SARS-CoV-2-exposed individuals by searching for monogenic inborn errors of immunity (IEI) and their phenocopies. We deciphered the pathogenesis of critical COVID-19 pneumonia and multisystemic inflammatory syndrome in children (MIS-C) in ~15% and 2% of cases, respectively, thereby revealing general mechanisms of severe disease. We also defined neuro-COVID-19 genetically and immunologically in one child, while we delineated the immunological mechanisms of COVID-toes in healthy children and young adults, paving the way for their genetic study. Understanding the human genetic and immunological basis of resistance to SARS-CoV-2 infection, long COVID, and myocarditis post mRNA vaccination, has been challenging and investigations remain ongoing. This work highlights the power of patient-based basic research and large-scale international collaborative efforts to discover human genetic and immunological drivers of infectious disease phenotypes, with implications for the timely development of new medical strategies before the next pandemic arrives.