The process of humanizing mice requires the transfer of 17-19 week old human fetal tissue into young mice, 6-8 weeks of age, with weakened immune systems. If a mouse with a normal immune system received human tissue, it would start to reject the tissue immediately after the transfer because its immune system would recognize the added tissue as foreign. This process, graft rejection, also happens in humans who receive incompatible organ transplants. Therefore, researchers use mice with a genetically weakened immune system for the humanization procedure. These genetically immunosuppressed mice tolerate the presence of foreign human tissue for long enough to conduct experiments [].

Because a mouse's body is full of its own immune cells, it is essential to remove these cells to create "space" for the human immune cells to populate. To do this, the mice are subjected to a sub-lethal dose of irradiation. Next, to create a niche where the cells can be constantly replenished, the scientists make a small surgical incision to implant human fetal liver and thymus tissue underneath the mouse's kidney. Finally, human stem cells are injected directly into the mouse's blood. 17-20 weeks after this procedure, the reconstitution is considered complete when the cells have divided sufficiently to populate their "home" in the mouse's body. A number of variations to the technique can be introduced depending on the experimental question that needs to be addressed, but most labs follow this general procedure, which is depicted in figure 1.