Childhood trauma and cumulative stressful life events often pre-date externalizing behaviors such as antisocial behavior and internalizing behaviors such as depression, both of which are risk factors for problem drinking and alcoholism. We have used data derived from parental self-report questionnaires in a birth cohort of approximately 7000 Caucasian girls and boys from the Avon Longitudinal Study of Parents and Children (ALSPAC), U.K. Mothers were recruited in early pregnancy and data is available on their children up to age 8 years. We have genotyped the children's DNA for functional polymorphisms in three genes: monoamine oxidase A (MAOA-LPR), serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met). In both sexes, exposure to family adversity and stressful life events in the first three years of life predicted behavioral disinhibition at age 4, persisting until at least age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity.(Enoch et al, 2010). Maternal depression and stressful life events increased the odds of high emotionality in children but there were no main or interactive effects of COMT Val158Met (Evans et al, 2009) or 5-HTTLPR (Araya et al, 2009) on behavior. In the Southwestern American Indian sample we found that the MAOA-LPR low activity allele was significantly associated with alcoholism, particularly antisocial alcoholism, only in women who had been exposed to childhood sexual abuse. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women (Ducci et al, 2008). In the African American men we found that exposure to childhood trauma predicted substance dependence. Severe childhood trauma predicted polysubstance dependence. The African Americans had four common haplotypes within the distal GABRA2 haplotype block: two that correspond to the Caucasian and Asian yin-yang haplotypes and two not found in other ethnic groups. One of the unique GABRA2 haplotypes predicted heroin addiction whereas the other haplotype was more common in controls and appeared to confer resilience to addiction after exposure to severe childhood trauma. Furthermore, variation in an intronic GABRA2 SNP (rs11503014) that is putatively implicated in exon splicing interacted with childhood trauma to influence addiction vulnerability, particularly to cocaine (Enoch et al, 2010). Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Alcohol and drug addiction are also associated with an increased risk of suicidality. FKBP5 is an HPA axis regulating gene at the level of the glucocorticoid receptor. Corticotropin releasing hormone (CRH) is a key regulator of the HPA axis through the CRH1 receptor. The actions of CRH are moderated by a high-affinity binding protein (CRHBP). In a study in African American men and women, we found that haplotypes of FKBP5 interacted with childhood trauma to predict suicide attempts: in the group exposed to high childhood trauma, 51% with two copies of the risk haplotype , 36% with one copy, and 20% with no copies had attempted suicide. In contrast, this haplotype conferred no suicide risk to individuals not exposed to childhood trauma (Roy et al, 2010). Three distal CRHBP SNPs (that we had previously associated with alcohol use disorders and anxiety disorders (Enoch et al, PLoS ONE, 2008) showed a significant interaction with childhood trauma to predict suicide attempt. In addition, there was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.49 in carriers of the FKBP5 rs3800373 major homozygote, 0.40 in carriers of the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes (Roy et al, submitted). The results of our studies suggest that, at least in individuals with substance dependence, FKBP5 and CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced significant childhood trauma.