The global shortage of transplantable organs remains a critical challenge in modern medicine. Every year, thousands of patients die while waiting for organ transplants due to the scarcity of suitable donors (https://www.organdonor.gov/learn/organdonation-statistics). In response to this crisis, researchers have turned to interspecies chimaeras as a promising solution for generating human-compatible organs in large animals. Interspecies blastocyst complementation, which involves the introduction of pluripotent stem cells (PSCs) from one species into the genetically modified blastocyst of another species, enables the growth of functional organs that could potentially be used in human transplantation (Figure 1A).

Recent advancements in identifying genes suitable for interspecies blastocyst complementation and overcoming interspecies chimerism barriers have led to an increasing number of reports on successful intra- and inter-species organogenesis (Table 1). While significant barriers remain, innovative approaches in synthetic biology and genetic engineering are progressively overcoming these obstacles (Figure 1B). At the same time, the ethical and regulatory challenges surrounding interspecies chimeras must not be overlooked. The potential for human cells to contribute to the brain or germline in animal hosts raises complex moral questions that need to be addressed before these technologies can be applied clinically. This review aims to provide a comprehensive overview of the latest developments in interspecies chimerism, focusing on organ generation and tissue repair, while discussing the technical, ethical, and regulatory challenges that accompany these advancements.