An updated paradigm for IUHCT. After the early successes of IUHCT in severe combined immunodeficiency and bare lymphocyte syndrome, subsequent efforts in immunologically normal fetuses failed to achieve sufficient tolerance and engraftment for therapeutic cure. These setbacks prompted a return to large and small animal studies over the past 2 decades to better understand and circumvent the barriers to successful clinical translation. This has yielded an updated paradigm for the IUHCT to guide renewed efforts.