Simple Summary Transforming Growth Factor-beta (TGF-beta) signaling is crucial to maintain tissue homeostasis. Alterations in TGF-beta signaling impact tissue functions and favor the development of diseases, including cancer. In hepatocellular carcinoma (HCC), the most frequent liver tumor, TGF-beta plays a dual role, acting as a tumor-suppressor at early stages but contributing to tumor progression at late stages. TGF-beta can also act on the stroma, favoring progression and driving immune evasion of cancer cells. Therefore, inhibiting the TGF-beta pathway may constitute an effective option for HCC treatment. However, its inhibition in the wrong patients could have negative effects. To overcome this obstacle, it is mandatory to identify relevant biomarkers of the status of TGF-beta signaling in HCC. In this review we summarize the functions of TGF-beta in HCC and the available strategies for targeting TGF-beta signaling. We also present the clinical results of the use of TGF-beta inhibitors and their future in HCC. Transforming Growth Factor-beta (TGF-beta) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-beta signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-beta plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-beta can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-beta pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-beta inhibitory therapies. Here we review the functions of TGF-beta on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-beta signaling for cancer therapy. We also summarize the clinical impact of TGF-beta inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.