Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients. The liver, continuously exposed to food and microbial antigens from the intestine, avoids autoimmune damage through the use of specialized mechanisms of immune tolerance. In the context of cancer, myeloid-derived suppressor cells profit the intrinsic tolerogenic properties of the liver to accumulate and exert various immune-suppressive and tumor-promoting mechanisms which go from inducing immune cell dysfunction to supporting the generation of liver metastases. In this review, we seek to describe the phenotype, function, accumulation and therapeutic targeting of hepatic myeloid-derived suppressor cells both in preclinical settings and in the context of human hepatocellular carcinoma.