Simple SummaryMature T- and NK-cell leukemia/lymphoma (MTCL/L) are a heterogeneous group of rare, mostly poor prognostic neoplastic entities. In the past, immunotherapeutic approaches have evolved, leading to prolonged survival of many patients with solid tumors or B-cell malignancies. As there are now many new immune system-based approaches for MTCL/L on the horizon, we aimed to summarize the distinct immunotherapeutic approaches. The specificity of an immunotherapeutic approach in MTCL/L is that the immune system must attack a cell from its own ranks. Within this review, we will present how the special forces of the immune systems must be educated and empowered to eradicate the secret defectors. Hereby, we will focus on monoclonal as well as bispecific antibodies, immune-checkpoint blockades, and CAR T cell therapies.AbstractMature T- and NK-cell leukemia/lymphoma (MTCL/L) constitute a heterogeneous group of, currently, 30 distinct neoplastic entities that are overall rare, and all present with a challenging molecular markup. Thus, so far, the use of first-line cancer treatment modalities, including chemotherapies, achieve only limited clinical responses associated with discouraging prognoses. Recently, cancer immunotherapy has evolved rapidly, allowing us to help patients with, e.g., solid tumors and also relapsed/refractory B-cell malignancies to achieve durable clinical responses. In this review, we systematically unveiled the distinct immunotherapeutic approaches available, emphasizing the special impediments faced when trying to employ immune system defense mechanisms to target ‘one of their own—gone mad’. We summarized the preclinical and clinical efforts made to employ the various platforms of cancer immunotherapies including antibody-drug conjugates, monoclonal as well as bispecific antibodies, immune-checkpoint blockades, and CAR T cell therapies. We emphasized the challenges to, but also the goals of, what needs to be done to achieve similar successes as seen for B-cell entities.