Medications and genetics have been identified as research priorities by NIAAA. The present application proposes to test two genetic-drug matching hypotheses to better understand heterogeneity among alcoholics. Previous basic science, treatment and genetic research suggests that active drinkers with the LL genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk factor for early onset alcoholism) will respond better to ondansetron than sertraline or placebo. Conversely, active drinkers with the SS or SL genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk factor for late onset alcoholism) will respond better to sertraline than ondansetron or placebo. The objective of this research is to match and mismatch serotonergic treatments to genetic polymorphic variants in a double-blind placebo controlled 2 x 2 design laboratory study where the 2 arms will be counterbalanced. The specific aims are to investigate: (1) whether LL-carriers receiving ondansetron results in a significant reduction in alcohol consumption during an alcohol self-administration experiment (ASAE) and during the period of treatment; (2) whether SL and SS-carriers receiving sertraline will result in a significant reduction in alcohol consumption during an ASAE and during the period of treatment; (3) examine mechanism of action for craving and subjective effects during the ASAE sessions: (4) whether there is a reduction in alcohol consumption during the ASAEs in the presence of the LG, and LA 5-HTTLPR variants and when LL participants receive ondansetron or when LL participants receive sertraline; (5) if the primary aims are moderated by the presence of the C (-1019) G polymorphism of the 5-HT1A gene promoter. We propose to randomize 132 non-treatment-seeking alcohol dependent participants based on their 5'-HTTLPR variant genotype (LL or SS/SL) into one of two counterbalanced arms: e.g. subjects in the first arm will first receive one drug (either 200mg/day of sertraline or ondansetron 0.5mg/day) for three weeks followed by an ASAE, then receive placebo for three weeks (this will be a single-blind portion to use as a comparison group and to wash out the pharmacodynamic effects of the first drug) followed by a second ASAE. Finally, participants will receive the second drug for three weeks followed by a third ASAE. Volunteers in the second arm will receive the same medications in a counter-balanced fashion. There will be a 1-week down titration after the first and third segments for all subjects. The long-term objective of this proposed research is to examine serotonergic treatment matching for alcohol dependence based on genotyping, and begin to investigate patient variation when matched prospectively with one serotonergic treatment or the other.