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Microbial community structure is highly sensitive to natural (e.g., drought, temperature, fire) and anthropogenic (e.g., heavy metal exposure, land-use change) stressors. However, despite an immense amount of data generated, systematic, cross-environment analyses of microbiome responses to multiple disturbances are lacking. Here, we present the Microbiome Stress Project, an open-access database of environmental and host-associated 16S rRNA amplicon sequencing studies collected to facilitate cross-study analyses of microbiome responses to stressors. This database will comprise published and unpublished datasets re-processed from the raw sequences into exact sequence variants using our standardized computational pipeline. Our database will provide insight into general response patterns of microbiome diversity, structure, and stability to environmental stressors. It will also enable the identification of cross-study associations between single or multiple stressors and specific microbial clades. Here, we present a proof-of-concept meta-analysis of 606 microbiomes (from nine studies) to assess microbial community responses to: (1) one stressor in one environment: soil warming across a variety of soil types, (2) a range of stressors in one environment: soil microbiome responses to a comprehensive set of stressors (incl. temperature, diesel, antibiotics, land use change, drought, and heavy metals), (3) one stressor across a range of environments: copper exposure effects on soil, sediment, activated-sludge reactors, and gut environments, and (4) the general trends of microbiome stressor responses. Overall, we found that stressor exposure significantly decreases microbiome alpha diversity and increases beta diversity (community dispersion) across a range of environments and stressor types. We observed a hump-shaped relationship between microbial community resistance to stressors (i.e., the average pairwise similarity score between the control and stressed communities) and alpha diversity. We used Phylofactor to identify microbial clades and individual taxa as potential bioindicators of copper contamination across different environments. Using standardized computational and statistical methods, the Microbiome Stress Project will leverage thousands of existing datasets to build a general framework for how microbial communities respond to environmental stress.