Ancient lakes are among the best archivists of past environmental change, having experienced more than one full glacial cycle, a wide range of climatic conditions, tectonic events, and long association with human settlements. These lakes not only record long histories of environmental variation and human activity in their sediments, but also harbor very high levels of biodiversity and endemism. Yet, ancient lakes are faced with a familiar suite of anthropogenic threats, which may degrade the unusual properties that make them especially valuable to science and society. In all ancient lakes for which data exist, significant warming of surface waters has occurred, with a broad range of consequences. Eutrophication threatens both native species assemblages and regional economies reliant on clean surface water, fisheries, and tourism. Where sewage contributes nutrients and heavy metals, one can anticipate the occurrence of less understood emerging contaminants, such as pharmaceuticals, personal care products, and microplastics that negatively affect lake biota and water quality. Human populations continue to increase in most of the ancient lakes’ watersheds, which will exacerbate these concerns. Further, human alterations of hydrology, including those produced through climate change, have altered lake levels. Co-occurring with these impacts have been intentional and unintentional species introductions, altering biodiversity. Given that the distinctive character of each ancient lake is strongly linked to age, there may be few options to remediate losses of species or other ecosystem damage associated with modern ecological change, heightening the imperative for understanding these systems.