Palaeogenomics has revolutionised our understanding of human population history at the biological and sociocultural level by analysing thousands of ancient human genomes sequenced from skeletal remains. Unfortunately, this approach requires destructive sampling of the skeletal remains, and thus can often be in conflict with the values of descendant communities and national heritage conservation policies. Although alternative sources of ancient human DNA have been sought, their utilisation requires prohibitive sequencing data volumes, or they are rare in the archaeological record, thus precluding large-scale studies. To circumvent these limitations, we will use a novel DNA source: ancient quids. Quids are wads of masticated plant fibres recovered from archaeological sites. Analogous to a buccal swab, an ancient quid contains traces of the chewer's, their oral microbiome's and the chewer's meals' DNA, as well as that of the plants used for its elaboration. Therefore, quid DNA can be used to simultaneously track human population history, dietary and microbiome shifts, pathogen prevalence and their interplay through time. We will use quid DNA to reconstruct the evolutionary history of the Indigenous peoples from the Americas, a continent where human evolutionary history is understudied, skeletal remains are rare, and the destructive sampling of such remains is often limited. In contrast to skeletal remains, quids are abundant in the American archaeological record and span from the Late Pleistocene to the Holocene and recent centuries. Through ancient quid DNA, we will reconstruct the genomic history of Indigenous Americans, their past lifeways and subsistence strategies, their health, and how these influenced each other throughout the three major historical transitions in the continent: the initial rapid peopling by hunter-gatherers, the emergence of complex agricultural societies and their demise during European colonisation.