As the fourth leading cause of cancer-related death in the world, liver cancer poses a major threat to human health. Although a growing number of therapies have been approved for the treatment of hepatocellular carcinoma in the past few years, most of them only provide a limited survival benefit. Therefore, an urgent need exists to identify novel targetable vulnerabilities and powerful drug combinations for the treatment of liver cancer. The advent of functional genetic screening has contributed to the advancement of liver cancer biology, uncovering many novel genes involved in tumorigenesis and cancer progression in a high-throughput manner. In addition, this unbiased screening platform also provides an efficient tool for the exploration of the mechanisms involved in therapy resistance as well as identifying potential targets for therapy. In this Review, we describe how functional screens can help to deepen our understanding of liver cancer and guide the development of new therapeutic strategies.