A clear message to emerge from the recent 6th International TNF Congress is that TNF-alpha, LT-alpha and possibly other TNF family members, are important integral mediators of the CNS stress response to threatened homeostasis and that either excessive or insufficient TNF-alpha production can have significant consequences upon correct CNS functioning. Experimental data are particularly relevant in light of recent evidence which shows some linkage between polymorphisms in the human TNF-alpha/LT-alpha locus and susceptibility to CNS infection and thus highlight such cytokine pathways as promising therapeutic targets for the management of certain CNS diseases. Judging by the significant advances that have been made recently in the field of cytokine neurobiology, and the currently explosive development of transgenic and gene mutant mouse models with which to probe the cellular and molecular mechanisms of TNF-alpha and LT-alpha action within the CNS, we can look forward to shortly understanding more precisely the important and diverse roles that these cytokines play in CNS health and disease.