Alcohol and nicotine use are together the largest preventable causes of morbidity and mortality in the United States. While there has been a steady decline of cigarette smoking in the US, in 2017 the 1-year prevalence of current smoking was 14%, with a disproportionate rate of use among individuals from disadvantagedbackgrounds. Regular alcohol use and misuse remains a persistent issue across a majority of Americans, and is associated with a range of medical issues including liver damage and neuropsychiatric impairments. Previous genetic association research has focused predominantly on individuals of European ancestry. We expand upon existing research by conducting a GWAS meta-analysis of alcohol and nicotine use across multiple ancestries. Our approach maximizes power for variant detection, allows evaluation of ancestry-specific variant effects, and provides greater fine-mapping resolution. We have conducted a meta-analysis in over 3.4 million individuals of diverse ancestry to discover genetic variation contributing to multiple stages of smoking including whether an individual has ever been a regular smoker (N=3,377,408 from 75 studies discovering 780 loci [404 novel]), age of initiation of regular smoking (N=731,870; 64 studies; 39 loci [30 novel]), cigarettes per day (N=782,790; 81 studies; 157 loci [103 novel]), smoking cessation (N=1,400,906; 742,222 studies, 112 loci [91 novel]), as well as drinks per week, a measure of alcohol consumption (N=2,896,131; 62 studies; 376 loci; [286 novel]). The largest non-European ancestry subset is composed of individuals of East Asian ancestry, with sample sizes ranging from N=62,943 for age of initiation of regular smoking to 293,145 for ever/never smoker status. We will report trans-ethnic discovery and evidence for ancestry-moderated variant effects, as well as heritabilities and utility of polygenic scores from this dataset.