TCDD is a highly immunosuppressive chemical that induces potent suppression of immune responses in laboratory animals. However, apart from the requisite role of the AhR and the identification of bone-marrow-derived cells as critical AhR-expressing targets, the specific cells and the underlying biochemical mechanisms by which TCDD disrupts immunological functions remain unclear. Recent data suggest that a new paradigm for the mechanism of immunotoxic action of TCDD may be more accurate, moving from one focused on the suppression of immune functions to one focused on the inappropriate activation of cells, leading to anergy or death, and the consequent premature termination of the immune response. Enhanced activation of B cells, DC and CD4+ T cells by TCDD has been described as well as the earlier disappearance of the latter two populations from peripheral lymphoid organs. Although much remains to be learned about how inappropriate cellular activation via the AhR induces immune suppression, deducing this mechanism of action and the signaling pathways involved, should lead to new insight into basic mechanisms of immune regulation.