The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the single-nucleotide polymorphism producing a valine-to-methionine substitution at codon 66 (val66met) of the BDNF gene was associated with childhood NE, in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. The children's parents completed clinical interviews as well as a measure of marital satisfaction. Children with at least one BDNF methionine (met) allele exhibited elevated NE when a parent had a history of depressive disorder or when relationship discord was reported by a parent. In contrast, this allele was associated with especially low NE when parental depression was absent and when the parental relationship was not discordant. Our findings suggest that the BDNF met allele confers increased child sensitivity to both positive and negative familial influences.