CD5 is a pan T cell marker also expressed at various developmental and activation stages on human B cells. CD5 is a well established negative regulator of TCR and BCR signalling. In the last years, great advances have been made in understanding the molecular mechanisms behind this regulatory function. Using animal models, it was demonstrated that increased expression of CD5 on either T cells or B cells protects against autoimmunity; as a consequence of an increase of the threshold needed for TCR- or a BCR-mediated activation following antigen recognition. CD5-positive cells may also prevent the emergence of autoimmunity by provision of cytokines such as IL-10. Although the physiological role of CD5 might be to control the generation of aberrant immune responses, the expansion of CD5+ lymphocytes may be deleterious. The other side of the coin is that in cancers, CD5 expression plays a role in the fate of tumour-specific T cells, rendering lymphocytes tolerant and unable to recognize and eliminate malignant cells. IL-10-producing B-cells may also inhibit anti-tumoural immune responses. An important issue is therefore to better understand the molecules produced by tolerogenic or immunogenic microenvironments that respectively turn on or downregulate CD5 expression, with potential therapeutic implications.