Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal of introns and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention of intronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulate pre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies. (C) 2010 Baishideng. All rights reserved.