Alcoholism and alcohol-related problems rank among the world’s major public health concerns. American Indians have historically experienced numerous problems with alcohol since its introduction into their culture by European settlers. Although tribes differ with regard to the use of alcohol Native Americans, as a group, have the highest alcohol-related death rates of all ethnic groups in the United States. However, how and why alcoholism is more prevalent in some Native American communities remains unclear. The overall objective of this research plan is to enhance understanding of the biological risk and protective factors related to alcohol dependence and alcohol-related problems in reservation dwelling Indians indigenous to San Diego county (collectively called Mission Indians). The studies proposed in this application extend our previous cross-sectional studies in Mission Indian adults. Additionally, longitudinal studies in Native American children and adolescents will also be extended in order to investigate specific genetic and environmental risk factors existing both prior to alcohol exposure and during the development of drinking patterns. The following four questions will be explored in this population (1) Can specific risk and protective factors for alcohol dependence be identified in this population? (2) Do Mission Indians have high rates of alcoholism because of a unique clinical course or an excess of concurrent affective, conduct or anxiety disorders? (3)Does exposure to high levels of alcohol in adolescence lead to increased risk for alcohol dependence as well as detrimental medical and psychological outcomes? (4) Are there specific genes that are associated with risk and protective factors for the development of alcohol dependence in Mission Indians? These studies have the potential to verify whether Native Americans have any specific biological/genetic, psychosocial or behavioral factors that may help to explain the high risk for alcoholism within the tribes evaluated. The identification of such variables may potentially be useful in the development of specific prevention and treatment programs for this population as well as other Native American tribes.