Alpine environments in South America occur essentially in the Andes, which extend along a latitudinal gradient between 11N in Colombia and 55S in Chile. The alpine biodiversity of the Andes is the richest in the world and it displays remarkable patterns of endemism, species radiations and morphological/physiological adaptations. In this article we aim at discussing the major biogeographical drivers of alpine biodiversity in the Andes and their consequent spatial patterns (i) in the past, (ii) at present, and (iii) in a near future under the influence of global change. Moreover, we briefly discuss the biogeography of smaller alpine environments in South America, that is, the Guayana highlands, Campos de Altitude and Tristan da Cunha Island. First, the evolution of the South American continent during the Mesozoic and Cenozoic greatly shaped biodiversity patterns in the Andes through mountain uplift and successive periods of geographic connectivity and isolation. Mountain building led to new niches that became available for colonization by both temperate and tropical species, while important topographic changes and the continental connection with North America provided either biotic corridors or sky islands. Second, Pleistocene glacial dynamics accelerated taxonomic diversification but also exacerbated extinction processes that substantially changed Andean biodiversity. Third, human activities have progressively influenced the structure and function of alpine ecosystems, leading to today’s Andean biogeography. Current drivers of biodiversity distribution can be described at three spatial scales. At the continental scale, latitudinal shifts create strong variations in temperature seasonality, influencing, for example, snow cover duration and generating distinctive adaptations from the North to the South. At the regional scale, rain shadow effects, the Humboldt Current and trade winds combine with topographical and bedrock variations to create hotspots of endemism such as are found in the Sierra Nevada de Santa Marta (Colombia) or alpine deserts with specific life forms such as are found in the Central Andes. At the local scale, the spatial distribution of species is extended through habitat amelioration by nurse/engineering plants. These unique alpine ecosystems are highly vulnerable to the combined effects of climate and land use changes. High-Andean biota will undoubtedly respond to these changes by either adaptation, local/regional migration, or extinction. Extinction is already occurring at alarming rates in many taxonomic groups. Finally, we predict that new threats, such as biotic invasions and the creation of non-analog communities will directly affect biodiversity responses