Strategies for cell replacement therapy have been guided by the success in the hematopoietic stem cell field. In this review, we discuss the basis of this success and examine whether this stem cell transplant model can be replicated in other systems where stem cell therapy is being evaluated. We conclude that identifying the most primitive stem cell and using it for transplant therapy may not be appropriate in all systems. We suggest alternative strategies such as progenitor cell replacement, inductive factors, bioengineering organs, in utero transplants, or any approach that takes advantage of the unique properties of the tissue and the stem cell type which, are more likely to provide effective functional replacement.