CD1 antigen presenting molecules are poorly polymorphic; this makes extremely attractive harnessing CD1-restricted T cells for clinical use, because their reactivity would be donor-unrestricted, hence universal. CD1d-restricted iNKT cells have been implicated in a number of pathological situations and are already exploited for clinical use, particularly in cancer immunotherapy. Clinical implications and exploitation of group 1 CD1 T cell responses are less explored, even though basic and pre-clinical studies are accumulating, suggesting intriguing pathophysiological involvements for these cells. Xenoreactive group 1 CD1 restricted T cells specific for bacterial lipid antigens have long been implicated in the immune control of infectious pathogens, particularly Mycobacterial ones, suggesting the generation of group 1 CD1-restricted protective lipid vaccines. New data are revealing the potential clinical relevance also for autoreactive group 1 CD1 restricted T cell responses directed against stress-related self-lipids, which may be involved in tumor immunesurveillance or autoimmunity, two conditions in which self-antigens are the targets of the immune response. Targeting or blocking recognition of self-lipid antigens may become viable therapeutic options in cancer and autoimmunity, respectively. Continuous investigation on fundamental aspects of group 1 CD1 restricted T cell response will fuel the promise of appropriate clinical translation.