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Hepatoblastoma is the most common primary liver malignancy in children less than 5 years of age. The incidence of this cancer is increasing but therapy for hepatoblastoma has not significantly changed and it is primarily managed with combinations of surgery and chemotherapy. Conventional chemotherapy regimens include cisplatin, as it is currently the most effective agent for this tumor. Unfortunately, with the current modalities, the prognosis for advanced-stage disease remains poor due to the high rate of recurrence and/or the development of chemoresistance. As the understanding of the pathophysiology of hepatoblastoma deepens, there is a burgeoning interest in developing novel therapeutic agents for hepatoblastoma, including targeted therapies. In the current review, we discuss the use of major signaling pathways and their effector molecules such as β-catenin, c-MET, mTOR, PIM kinases, and PLK1 as therapeutic targets. In addition, we explore various alternative pre-clinical approaches that have been described in hepatoblastoma, including immunotherapy, differentiation agents, micro-RNAs, and targeted drug delivery. Finally, we outline the therapies currently under investigation in pre-clinical and clinical settings that show promising preliminary results for hepatoblastoma treatment.