Big sagebrush, Artemisia tridentata Nuttall (Asteraceae), is the dominant plant species of large portions of semiarid western North America. However, much of historical big sagebrush vegetation has been removed or modified. Thus, regeneration is recognized as an important component for land management. Limited knowledge about key regeneration processes, however, represents an obstacle to identifying successful management practices and to gaining greater insight into the consequences of increasing disturbance frequency and global change. Therefore, our objective is to synthesize knowledge about natural big sagebrush regeneration. We identified and characterized the controls of big sagebrush seed production, germination, and establishment. The largest knowledge gaps and associated research needs include quiescence and dormancy of embryos and seedlings; variation in seed production and germination percentages; wet-thermal time model of germination; responses to frost events (including freezing/thawing of soils), CO2 concentration, and nutrients in combination with water availability; suitability of microsite vs. site conditions; competitive ability as well as seedling growth responses; and differences among subspecies and ecoregions. Potential impacts of climate change on big sagebrush regeneration could include that temperature increases may not have a large direct influence on regeneration due to the broad temperature optimum for regeneration, whereas indirect effects could include selection for populations with less stringent seed dormancy. Drier conditions will have direct negative effects on germination and seedling survival and could also lead to lighter seeds, which lowers germination success further. The short seed dispersal distance of big sagebrush may limit its tracking of suitable climate; whereas, the low competitive ability of big sagebrush seedlings may limit successful competition with species that track climate. An improved understanding of the ecology of big sagebrush regeneration should benefit resource management activities and increase the ability of land managers to anticipate global change impacts.