Induced pluripotent stem cells (iPSC) derived from somatic cells retain an epigenetic memory of their tissue of origin, which influences their differentiation potential. This study compares iPSC, nuclear transfer-derived pluripotent stem cells (ntESC), and embryonic stem cells (fESC) to determine the effects of reprogramming methods on epigenetic memory. iPSC generated by transcription factor-based reprogramming show residual DNA methylation signatures characteristic of their somatic tissue of origin, favoring differentiation along related lineages and restricting alternative fates. In contrast, ntESC show methylation patterns more similar to fESC. Epigenetic memory can be reset by differentiation, serial reprogramming, or treatment with chromatin-modifying drugs. The study also shows that iPSC derived from blood cells (B-iPSC) have higher hematopoietic potential than those from fibroblasts (F-iPSC), and that differentiation into hematopoietic lineages followed by reprogramming can enhance blood-forming potential. Treatment with chromatin-modifying agents like Trichostatin A (TSA) and 5-azacytidine (AZA) can also enhance blood-forming potential by reducing methylation at hematopoietic loci. These findings highlight the importance of epigenetic memory in iPSC and the need for improved reprogramming methods to achieve fully naive pluripotency.Induced pluripotent stem cells (iPSC) derived from somatic cells retain an epigenetic memory of their tissue of origin, which influences their differentiation potential. This study compares iPSC, nuclear transfer-derived pluripotent stem cells (ntESC), and embryonic stem cells (fESC) to determine the effects of reprogramming methods on epigenetic memory. iPSC generated by transcription factor-based reprogramming show residual DNA methylation signatures characteristic of their somatic tissue of origin, favoring differentiation along related lineages and restricting alternative fates. In contrast, ntESC show methylation patterns more similar to fESC. Epigenetic memory can be reset by differentiation, serial reprogramming, or treatment with chromatin-modifying drugs. The study also shows that iPSC derived from blood cells (B-iPSC) have higher hematopoietic potential than those from fibroblasts (F-iPSC), and that differentiation into hematopoietic lineages followed by reprogramming can enhance blood-forming potential. Treatment with chromatin-modifying agents like Trichostatin A (TSA) and 5-azacytidine (AZA) can also enhance blood-forming potential by reducing methylation at hematopoietic loci. These findings highlight the importance of epigenetic memory in iPSC and the need for improved reprogramming methods to achieve fully naive pluripotency.