This paper addresses the challenge of using non-equilibrium plasma as a therapeutic approach for diseases of body systems not readily accessible to plasma-generated factors. The role of plasma stimulation of the immune system is discussed as a conceivable mechanism to deliver effects. This is especially important for treatment of cancers since the pathogenesis and progression of cancers are directly influenced by immune function. By optimizing plasma parameters to induce immunogenic cell death in tumors locally, it is possible to trigger specific, protective immune responses systemically. The observations from in vitro and in vivo investigations on this subject are reviewed here. An in depth understanding of the interaction between plasma components and the cells of the immune system may provide necessary information for use of plasmas in treatment of many systemic diseases. The clinical implications of treating cancers with non-equilibrium plasma are considered. The paper also identifies some hurdles that must be overcome before plasma immunotherapy becomes a clinical reality.