Mainland Southeast Asia (MSEA) is an area with a long history of human occupation and great ethnolinguistic diversity. The earliest anatomically modern humans arrived ~65 thousand years ago, while presently it has a population size of ~263 million people speaking ~229 languages belonging to five major language families: Austroasiatic (AA), Austronesian (AN), Tai-Kadai (TK), Hmong-Mien (HM), and Sino-Tibetan (ST). Analyses of genome-wide data can provide rich insights into reconstructing human genetic population history, but there is a paucity of genome-wide data from MSEA (mostly limited to the majority groups such as the Kinh and Thai). The goal of this thesis was to analyze newly-genotyped genome-wide data (encompassing ~600 thousand SNPs) from an extensive, detailed sample of ethnolinguistic groups from Vietnam, Thailand, and Laos, encompassing all five major MSEA language families, in order to reconstruct their genetic history and relationships with cultural variation. In Chapter I, I analyzed data from 259 individuals from the Kinh and 21 Vietnamese ethnolinguistic groups. In contrast to previous studies suggesting that genetic diversity in Vietnam largely reflects internal diversification and isolation, I found evidence for different sources of genetic diversity in different linguistic groups, extensive contact between groups, and a likely case of language shift involving AN-speaking groups. In Chapter II, I analyzed data from 463 individuals from 33 ethnolinguistic groups together with 3 published groups (including the Thai), hence in total 36 groups from Thailand and Laos. I found fine-scale genetic structure for the major TK and AA groups according to their linguistic branches, and different levels of local interaction with other linguistic groups in geographical proximity. This diverse structure was also influenced by South Asian admixture, detected in several different linguistic groups from central and southern Thailand, dated to ~600-1000 years ago. This admixture date, together with the geographical distribution of these groups, suggests that the South Asian influence corresponds to the Ayutthaya kingdom period (1350-1767 AD), when there was extensive interactions and political and trading networks between people from MSEA and South Asia.:SUMMARY p.1 ZUSAMMENFASSUNG p.10 CHAPTER I p.20 Extensive ethnolinguistic diversity in Vietnam reflects multiple sources of genetic diversity CHAPTER II p.68 Reconstructing the human genetic history of mainland Southeast Asia: insights from genome- wide data from Thailand and Laos REFERENCES p.111 ACKNOWLEDGMENTS p.114 CURRICULUM VITAE p.115 DECLARATION OF INDEPENDENCE p.117 AUTHOR CONTRIBUTION STATEMENT p.118