Understanding cancer at the genetic level had gained significant attention over the last decade since the human genome was first sequenced in 2001. For hepatocellular carcinoma (HCC) a number of genome-wide profiling studies have been published. These studies have provided us with gene sets, based on which we can now classify tumors and have an idea about the likely clinical outcomes. In addition to that, genomic profiling for HCC has provided us a better understanding of the carcinogenesis process and identifies key steps at multiple levels (i.e. Genetics, molecular pathways) that can be potential targets for treatment and prevention. Although still an incurable disease, unresectable HCC has one proven systemic therapy, sorafenib, and many under active investigation. With advancement in technology and understanding of hepatocarcinogenesis, scientists hope to provide true personalized treatment for this disease in the near future. In this review article we discuss advances in understanding genetics and pathogenesis of HCC and the currently available and ongoing trials for targeted therapies. These emerging therapies may guide the development of more effective treatments or possibly a cure for HCC.