CD5 was one of the first surface receptors described for mouse and human T lymphocytes. Since then, it has been found to be highly expressed by regulatory T cells and a subpopulation of regulatory B cells, to be physically associated with the T- and B-cell antigen receptors, to negatively modulate TCR- and BCR-mediated signals, and to bind certain pathogen-associated molecular patterns. These findings position CD5 as an attractive target for developing immunotherapies aimed at either boosting or dampening ongoing immune responses. Here the available data on the function of CD5 and its involvement in the regulation of immune responses in health and disease are reviewed, as well as the evidence for and future challenges in developing therapeutic strategies aimed at targeting CD5 for autoimmune diseases, cancer, and infections.