One of the most enduring and stirring debates in archeology revolves around the role humans played in the extinction of large terrestrial mammals (megafauna) and other animals near the end of the Pleistocene. Rather than seeking a prime driver (e.g., climate change, human hunting, disease, or other causes) for Pleistocene extinctions, we focus on the process of human geographic expansion and accelerating technological developments over the last 50,000 years, changes that initiated an essentially continuous cascade of ecological changes and transformations of regional floral and faunal communities. Human hunting, population growth, economic intensification, domestication and translocation of plants and animals, and landscape burning and deforestation, all contributed to a growing human domination of earth's continental and oceanic ecosystems. We explore the deep history of anthropogenic extinctions, trace the accelerating loss of biodiversity around the globe, and argue that Late Pleistocene and Holocene extinctions can be seen as part of a single complex continuum increasingly driven by anthropogenic factors that continue today.