More than eighteen years have passed since the rst deriva on of human embryonic stem cells (ESCs), but their clinical use is s ll met with several challenges, such as ethi- cal concerns regarding the need of human embryos, ssue rejec on a er transplanta- on and tumour forma on. The genera on of human induced pluripotent stem cells (iPSCs) enables the access to pa ent-derived pluripotent stem cells (PSCs) and opens the door for personalized medicine as ssues/organs can poten ally be generated from the same gene c background as the pa ent recipients, thus avoiding immune rejec ons or complica on of immunosuppression strategies. In this regard, successful replacement, or augmenta on, of the func on of damaged ssue by pa ent-derived di eren ated stem cells provides a promising cell replacement therapy for many dev- asta ng human diseases. Although human iPSCs can proliferate unlimitedly in culture and harbour the poten al to generate all cell types in the adult body, currently, the func onality of di eren ated cells is limited. An alterna ve strategy to realize the full poten al of human iPSC for regenera ve medicine is the in vivo ssue genera on in large animal species via interspecies blastocyst complementa on. As this technology is s ll in its infancy and there remains more ques ons than answers, thus in this re- view, we mainly focus the discussion on the conceptual framework, the emerging technologies and recent advances involved with interspecies blastocyst complemen- ta on, and will refer the readers to other more in-depth reviews on dynamic pluripo- tent stem cell states, genome edi ng and interspecies chimeras. Likewise, other emerging alterna ves to combat the growing shortage of human organs, such as xenotransplanta on or ssue engineering, topics that has been extensively reviewed, will not be covered here.