MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.