The full story of what surface markers mean about the cells on which they reside twists and turns as the days go by, with previously accepted “truth” changing in light of new findings. Such is the case with CD5, a surface marker on most murine T cells, many thymocytes, and a subset of B cells. The precise role of CD5 in the murine and human immune responses has been a matter of intense speculation for many years. Recent work suggests that CD5 may have a fine-tuning or suppressive effect on signaling through the antigen receptors on both B and T cells. These CD5+ B cells were initially thought to be a major source of autoantibodies and/or “natural antibodies,” targeting broad arrays of carbohydrate and protein antigens. More recent studies support the latter contention—CD5+ B cells do produce “natural antibodies,” but the former is far from true—CD5+ B cells are not the major source of autoantibodies. In fact, CD5 may be a major negative influence on antigen receptor driven–B-cell function and may serve to control autoimmunity rather than encourage it. Furthermore, another subset of CD5+ B cells may represent a distinct regulatory population. CD5 expression is noted on more than three fourths of all T-cell lymphomas. CD5 may be a receptor of pathogen-associated molecular patterns; CD5 may be a marker of decreased dependence of B cells on certain circulating factors. Elevated levels of CD5 are found in a number of autoimmune disorders. Thus, although the precise mechanism is unclear, there is at the very least circumstantial evidence of a role for CD5 in the pathogenesis of autoimmunity and perhaps T cell–derived lymphoid malignancy. New findings put old claims to rest and open up new avenues for research, both basic and clinical, with therapeutic applications not far behind.