Disease and accompanying inflammation are uncommon outcomes of viral infection in humans. Clinical inflammation occurs if steady-state cell-intrinsic and leukocytic immunity to viruses fails. Inflammation attests to the attempts of newly recruited and activated leukocytes to resolve infection in the blood or tissues. In the confusing battle between a myriad of viruses and cells, studies of human genetics can separate the root cause of inflammation and disease from its consequences. Single-gene inborn errors of cell-intrinsic or leukocytic immunity underlying diverse infections in the skin, brain, or lungs can help to clarify the human determinants of viral disease. The genetic elucidation of immunological deficits in a single patient with a specific vulnerability profile can reveal mechanisms of inflammation and disease that may be triggered by other causes, inherited or otherwise, in other patients. This human genetic dissection of viral infections is giving rise to a new biology and a new medicine.