Immunotherapy approaches have advanced rapidly in recent years. While the greatest therapeutic advances so far have been achieved with T cell therapies such as immune checkpoint blockade and CAR-T, recent advances in NK cell therapy have highlighted the therapeutic potential of these cells. Chronic lymphocytic leukemia (CLL), the most prevalent form of leukemia in Western countries, is a very immunosuppressive disease but still shows significant potential as a target of immunotherapy, including NK-based therapies. In addition to their antileukemia potential, NK cells are important immune effectors in the response to infections, which represent a major clinical concern for CLL patients. Here, we review the interactions between NK cells and CLL, describing functional changes and mechanisms of CLL-induced NK suppression, interactions with current therapeutic options, and the potential for therapeutic benefit using NK cell therapies.