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The future vision of many cell-based regenerative therapies is to repair or replace damaged tissues by grafting in healthy cell populations. In some cases, this requires that the grafted population seamlessly integrate with the host tissues to generate a fully functional structure. Intriguingly, evidence from mammalian and amphibian model systems suggest that the ability of a graft to integrate into the host site is dependent on the positional information in both tissues, and that regeneration and integration do not appear to be necessarily coupled processes. In this chapter, we discuss the differences in the positional memory in the cell types that contribute to regenerating mammalian and amphibian organs, and how they impact the process of tissue integration. In addition, we dissect the potential causes of integration defects in cell-based regenerate therapies and present methods that could be utilized to overcome these challenges in specific tissue types.