Hepatocellular carcinoma (HCC) is the second cause of cancer-related mortality. The diagnosis of HCC depends mainly on -fetoprotein, which is limited in its diagnostic and screening capabilities. There is an urgent need for a biomarker that detects early HCC to give the patients a chance for curative treatment. New targets of therapy could enhance survival and create future alternative curative methods. In silico analysis provides both; discovery of biomarkers, and understanding of the molecular pathways, to pave the way for treatment development. This review discusses the role of in silico analysis in the discovery of biomarkers, molecular pathways, and the role the author has contributed to this area of research. It also discusses future aspirations and current limitations. A literature review was conducted on the topic using various databases (PubMed, Science Direct, and Wiley Online Library), searching in various reviews, and editorials on the topic, with overviewing the author's own published and unpublished work. This review discussed the steps of the validation process from in silico analysis to in vivo validation, to incorporation into clinical practice guidelines. In addition, reviewing the recent lines of research of bioinformatic studies related to HCC. In conclusion, the genetic, molecular and epigenetic markers discoveries are hot areas for HCC research. Bioinformatics will enhance our ability to accomplish this understanding in the near future. We face certain limitations that we need to overcome.