Mitochondria are critical organelles in cells involved in various cell signaling pathways and physiological functions, including proliferation, differentiation, apoptosis, and necrosis. Due to the increasing number of patients who resist immunotherapy, an improvement in these approaches is necessary. Many studies have considered mitochondria to be a suitable target in modern immunotherapy. In this chapter, we briefly reviewed the potential of mitochondria in immunotherapy approaches. In the tumor microenvironment (TME), targeting mitochondria and cell metabolism both in tumor cells and immune cells can change the diversity and functions of immune cells like T lymphocytes, macrophages, and natural killer cells (NKs). Targeting mitochondrial oxidation and phosphorylation (OXPHOS) also correlates with tumor cell antigen presentation and immunogenicity. Some studies targeted mitochondria alongside conventional immunotherapy approaches like immune checkpoints programmed cell death protein 1 (PD-1) and its ligand PD-L1 blockade and chimeric antigen receptor T cells (CAR-T) cell therapy. Targeting mitochondria alongside checkpoint inhibitors was shown to decrease immune resistance and, in CAR-T cell therapy, could boost efficiency. Despite the promising results, some contrasts exist between studies that question the efficacy of targeting OXPHOS and mitochondria. Although this approach is currently in its early stages of development, it has the potential to fulfill the rising needs of immunotherapy with more research and development, as well as the assistance of innovative therapeutic tactics such as precision medicine and targeted drug delivery.