Cancer stem cells (CSCs), also called tumor-initiating cells, are a minor subpopulation of cells within tumors that possess features of both stem cells and tumor cells, including the ability to self-renew and differentiate. CSCs immeasurably contribute to tumor progression by rendering tumor growth, metastasis, drug resistance, relapse, and immune evasion; therefore, targeting these cells could be a feasible approach and open new horizons for cancer-targeted therapies, particularly immunotherapies. The explosive success of immunotherapies has conspicuously revolutionized cancer treatment, bringing realistic hopes for patients; however, some patients may not benefit from these therapies. Over the past 10 years, immunotherapeutic strategies targeting CSCs have been a prominent topic in the field of immuno-oncology. This chapter begins by providing a concise overview of cancer stem cell biology. Subsequently, it offers a methodical and thorough explanation of cancer immunotherapy, ensuring a comprehensive understanding. Afterward, the chapter focuses on immunotherapeutic strategies that target CSCs, including immune checkpoint blockade, bispecific antibodies, natural killer T cell immunotherapy, natural killer cell immunotherapy, macrophage immunotherapy, T cell immunotherapy, nano-immunotherapy, cancer vaccines, and oncolytic virotherapy. It also highlights the therapeutic implications of CSCs-targeted immunotherapies, and how these therapies can be leveraged in the framework of translational research.