Introduction: Hepatocellular carcinoma (HCC) is a significant problem globally because of viral infections and the increasing incidence of obesity and fatty liver disease. However, it is difficult to treat because its inherent genetic heterogeneity results in activation of numerous signaling pathways. Kinases have been targeted for decades with varying results, but the development of therapeutic resistance is a major challenge. Areas covered: The key roles of the RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1, TP53 microRNAs (miRs) as therapeutic targets are discussed and we suggests novel approaches for targeting miRs or their downstream targets to combat HCC. We performed literature searches using the Medline Database from 2000 to the present. Expert opinion: The involvement of RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC and TP53 pathways as drivers of the disease and drug resistance is a challenge. Moreover, miRs regulate the expression of key genes in these pathways. What we and others are proposing is the prospect of targeting miRs and their downstream targets to improve conventional approaches to treat HCC. Combination approaches are often promising because multiple signaling pathways are deregulated due to diverse mutations and events.