Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.