Susceptibility to mycobacterial disease leads to severe clinical infections and has been associated with mutations in proteins involved in interferon-gamma signalling. In the July 13 Science, Dupuis et al., from the Hôpital Necker-Enfants Malades in Paris, report the identification of a mutation in the human STAT1 gene that affects susceptibility to mycobacterial but not viral disease (Science 2001, 293:300-303). The heterozygous germline mutation, causing a leucine to serine substitution (L706S), affects STAT1 phosphorylation and nuclear accumulation upon stimulation by interferons. Transfection studies showed that the L706S allele exerts a dominant-negative affect on the wild-type STAT1 allele in inducing gamma-activating factor (GAF) transcriptional activity. The clinical phenotype of the STAT1-mutant patients suggests that anti-mycobacterial immunity involves specific STAT1-dependent interferon-gamma signalling pathways.