Complex areas of scientific endeavor may sometimes benefit from a theoretical and/or reductionist approach to guide the direction of future experiments, perhaps best illustrated by the field of cosmology. The field of immunology in general, and transplantation immunology in particular, is certainly complex. This commentary draws attention to a theory that proposes an alternative role for MHC molecules, placing them central to the process of tolerance induction, with major implications for transplantation and all fields of immunology.