The original concept of contrasuppression (CS) is evident in many immunoregulatory mechanisms. Inhibition of suppressor activity – CS – may be critical in microbial infection and autoimmunity. The major cellular interactions involved in suppression are the CD25⁺ FoxP3⁺ CD4⁺ T regulatory cells, programmed death‐1 (PD‐1) : PD‐L1/L2 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) : CD80/86 pathways. These cellular functions are affected by dendritic cells (DC) and a complex array of cytokines of which interleukin (IL)‐2, IL‐10, IL‐6 and transforming growth factor‐β (TGF‐β) are especially significant. Inhibition of regulatory cells, suppressor pathways or cytokines, is consistent with CS and can be attributed to IL‐6, IL‐2, PD‐1 or PD‐L‐1 antibodies, blockade of CTLA‐4 : CD80/86 pathway, inhibition of CD40–CD40L pathways, and TGF‐β, IL‐10 antibodies. Contrasuppression may regulate innate immunity by Toll‐like receptor expressed not only in non‐cognate DC, monocytes, natural killer cells and γδ T cells but also in adaptive T cells. Furthermore, cross‐talk between innate and adaptive immunity may be facilitated by contrasuppressor activity.