This study investigates the reprogramming mechanism in somatic cell nuclear transfer (SCNT) of monkeys and introduces a trophoblast replacement (TR) method to improve cloning efficiency. The authors found that SCNT monkey blastocysts exhibit widespread decreases in DNA methylation and loss of imprinting in maternally imprinted genes, which persists until E17 and in full-term placentas. These defects lead to developmental failures in SCNT embryos, with most fetuses losing viability around day 40 of gestation. To address these issues, the authors developed a TR method, where the trophoblasts of SCNT embryos are replaced with those of intracytoplasmic sperm injection (ICSI) embryos. This approach successfully cloned a healthy male rhesus monkey, demonstrating the potential of TR in improving primate cloning efficiency. The study also highlights the importance of maintaining DNA methylation at imprinted gene loci during SCNT and suggests that somatic cells with better maintenance of DNA methylation may be more suitable donors for efficient cloning.This study investigates the reprogramming mechanism in somatic cell nuclear transfer (SCNT) of monkeys and introduces a trophoblast replacement (TR) method to improve cloning efficiency. The authors found that SCNT monkey blastocysts exhibit widespread decreases in DNA methylation and loss of imprinting in maternally imprinted genes, which persists until E17 and in full-term placentas. These defects lead to developmental failures in SCNT embryos, with most fetuses losing viability around day 40 of gestation. To address these issues, the authors developed a TR method, where the trophoblasts of SCNT embryos are replaced with those of intracytoplasmic sperm injection (ICSI) embryos. This approach successfully cloned a healthy male rhesus monkey, demonstrating the potential of TR in improving primate cloning efficiency. The study also highlights the importance of maintaining DNA methylation at imprinted gene loci during SCNT and suggests that somatic cells with better maintenance of DNA methylation may be more suitable donors for efficient cloning.