Hepatocellular carcinoma (HCC) is one of one of the most frequent liver cancers and the fourth leading cause of cancer-related mortality worldwide. Current treatment options such as surgery, neoadjuvant chemoradiotherapy, liver transplantation, and radiofrequency ablation will benefit only a very small percentage of patients. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The aim of our study is to present the currently ongoing clinical trials and to evaluate the efficacy of immunotherapy in HCC. In this paper, we demonstrate that combination of different immunotherapies or immunotherapy with other modalities results in better overall survival (OS) and progression-free survival (PFS) compared to single immunotherapy agent. Another objective of this paper is to demonstrate and highlight the importance of tumor microenvironment as a predictive and prognostic marker and its clinical implications in immunotherapy response.