HLA-G,-E and -F are important regulators of the immune system, and their role in tumour immunology is attracting a steadily growing interest. The upregulation of HLA-G, -E and -F following interferon-γ stimulation suggests that non-classical HLA class I molecules may be involved in negative feedback responses to potentially harmful pro-inflammatory responses. Inflammation is also one of the hallmarks of cancer. While inflammatory responses are required to eliminate cancer cells, they also trigger strong immuno-regulatory mechanisms that limit the recognition of malignant cells by the immune system, hence favouring tumour suppression. Thus, tumour results in the recruitment strongly immunosuppresive cells such as Tregs, myeloid-derived supressor cells and tumour infiltrating macrophages. Non-classical HLA class I molecules constitute another means whereby malignant cells escapes immune-surveilance. Indeed, these molecules inhibit the activity of the immune system by binding to inhibitory receptors expressed by effector cells, hence suppressing their functions or inducing their apoptotic demise. Thus, the molecules might become an important target for anticancer immunotherapy. Interfering with the functions of non-classical HLA class I molecules might robustly boost the antineoplastic potential of cytotoxic effectors while antagonizing the activity of intrinsically immunosuppressive cells. The specific mechanisms whereby these molecules control excessive inflammation are currently under investigation for theurapeutic purposes, not only in the context of anticancer immunotherapy.