Liver cancer is the sixth-most-common cancer overall but the third-most-frequent cause of cancer death. Among primary liver cancers, hepatocellular carcinoma (HCC), the major histological subtype, is associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Although previous studies have revealed that certain genetic and epigenetic changes, such as TP53 and β-catenin mutations, occur in HCC cells, the pathogenesis of this cancer remains obscure. Functional genomic approaches—including genome-wide association studies, whole-genome and whole-exome sequencing, array-based comparative genomic hybridization, global DNA methylome mapping, and gene or noncoding RNA expression profiling—have recently been applied to HCC patients with different clinical features to uncover the genetic risk factors and underlying molecular mechanisms involved in this cancer's initiation and progression. The genome-wide analysis of germline and somatic genetic and epigenetic events facilitates understanding of the pathogenesis and molecular classification of liver cancer as well as the identification of novel diagnostic biomarkers and therapeutic targets for cancer.