A challenge for the field of hemophilia A gene therapy, which provides context for this review, will be to understand to what extent these apparent inflammatory phenomena, as well as the decline in FVIII expression reported in one trial [8], result from immune mechanisms or from mechanisms that are not purely immune in origin (e.g., constraints of synthesis of factor VIII in hepatocytes rather than liver sinusoidal endothelial cells; natural senescence and turnover of hepatocytes) and what mitigating strategies will best balance benefit and risk. This evidence concerns the gene F8 and hemophilia A.