Alternative splicing of precursors messenger RNA (pre-mRNA) is commonly used to increase the diversity of messenger RNAs expressed by the genome in normal multicellular organisms. Dysregulation of alternative splicing underlies a number of human diseases, including cancers. Increasing evidence supports the important role of this expansive layer of gene regulation in hepatocarcinogenesis. Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide because of its aggressive property and limited therapeutic options. Studies suggest that aberrant alternative splicing promotes generation of oncogenic variants in HCC, whereas tumor suppressors are self-inactivated by aberrant alternative splicing in HCC. Moreover, different spliced variants of the same gene can display distinct and even antagonistic biological functions in HCC. As a result, inhibiting the splicing of oncogenic variants and the self-inactivation of tumor suppressors are likely to be new therapy strategies. This review provides a perspective of the emerging evidence of both alternative splicing as a critical mechanism for the development of HCC and that potential cross-talk through signaling pathways among different variants might aid in the development of novel molecular targets of HCC.