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Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and a leading cause of cancer-related mortality. Unfortunately, the majority of HCC patients present with advanced disease, when locoregional curative strategies are no longer applicable. On the other hand, early, HCCs proved to be resistant to conventional chemotherapies, and drugs targeting specific growth factor signaling pathways tested over the past decade have not succeeded in clinical trials. The molecular heterogeneity of HCCs and the lack of biomarker-based patient stratification strategies may underlie the failure of most of these trials. HCCs usually develop on a background of chronic liver injury and regeneration, inflammation, and fibrosis, features that promote tumor hypervascularity, the other histologic hallmark of this neoplasia. Indeed, the fibrotic and immune microenvironment plays a key role in pathogenic angiogenesis and HCC development and progression. This tenet is supported not only by experimental evidence, but also by the fact that the only therapeutic agents showing clinical efficacy in advanced HCC are those directed toward the interaction of HCC with its microenvironment (ie, anti-angiogenic multikinase inhibitors such as sorafenib, and immune checkpoint inhibitors such as antibodies targeting programmed cell death receptor 1 and its ligand).