This study investigates the epigenetic memory of induced pluripotent stem cells (iPSCs) derived from different tissues using somatic cell nuclear transfer (SCNT) and transcription factor-based reprogramming. The authors found that iPSCs derived from blood cells retain DNA methylation signatures characteristic of their somatic tissue of origin, which influences their differentiation potential. These iPSCs are more likely to differentiate along lineages related to the donor cell, while restricting alternative cell fates. In contrast, iPSCs derived from fibroblasts show more similarities to embryonic stem cells (ESCs) in terms of differentiation potential and methylation patterns. The study also demonstrates that the epigenetic memory can be reset by differentiation and serial reprogramming, or by treatment with chromatin-modifying drugs. The findings highlight the importance of understanding the epigenetic heterogeneity of iPSCs and suggest that methods to ensure complete reprogramming of somatic cells to a fully naïve state are necessary for optimal applications in disease modeling and treatment.This study investigates the epigenetic memory of induced pluripotent stem cells (iPSCs) derived from different tissues using somatic cell nuclear transfer (SCNT) and transcription factor-based reprogramming. The authors found that iPSCs derived from blood cells retain DNA methylation signatures characteristic of their somatic tissue of origin, which influences their differentiation potential. These iPSCs are more likely to differentiate along lineages related to the donor cell, while restricting alternative cell fates. In contrast, iPSCs derived from fibroblasts show more similarities to embryonic stem cells (ESCs) in terms of differentiation potential and methylation patterns. The study also demonstrates that the epigenetic memory can be reset by differentiation and serial reprogramming, or by treatment with chromatin-modifying drugs. The findings highlight the importance of understanding the epigenetic heterogeneity of iPSCs and suggest that methods to ensure complete reprogramming of somatic cells to a fully naïve state are necessary for optimal applications in disease modeling and treatment.