Normothermic machine perfusion (NMP) is emerging as a promising technique for organ preservation, evaluation, and scientific research, offering the potential to enhance the viability and function of donor organs. To fully harness the benefits of NMP, sustained long–term NMP (LNMP) at 36℃ for periods exceeding 24 h is required. However, the development of stable LNMP devices is hindered by our limited understanding of ex vivo liver physiology. This review synthesizes insights from clinical and experimental studies to highlight the knowledge gaps associated with the impact of the absence of various organs or systems on isolated livers during ex vivo perfusion. Additionally, it discusses liver injuries and adverse events documented in published liver LNMP studies, elucidating their underlying mechanisms. By analyzing these findings, the paper proposes a series of recommendations to establish a more stable LNMP platform, aiming to optimize the outcomes of liver preservation and expand the applications of NMP in clinical practice and research.