The human gut microbiome, a complex ecosystem, significantly influences host health, impacting crucial aspects such as metabolism and immunity. To deepen our comprehension and control of the molecular mechanisms orchestrating the intricate interplay between gut commensal bacteria and human health, the exploration of genome engineering for gut microbes is a promising frontier. Nevertheless, the complexities and diversities inherent in the gut microbiome pose substantial challenges to the development of effective genome engineering tools for human gut microbes. In this comprehensive review, we provide an overview of the current progress and challenges in genome engineering of human gut commensal bacteria, whether executed in vitro or in situ. A specific focus is directed towards the advancements and prospects in cargo DNA delivery and high-throughput techniques. Additionally, we elucidate the immense potential of genome engineering methods to deepen our understanding of the human gut microbiome and engineer the microorganisms to enhance human health.