The weedy Setaria species (giant, green, yellow, knotroot, and bristly foxtail) compose one of the worst weed groups interfering with world agriculture and in other disturbed and managed habitats. These species, together with their crop counterparts (foxtail millet, korali), form the foxtail species-group (spp.-gp). Five successive waves of Setaria spp. invasion from preagricultural times to the present have resulted in widespread infestation of the disturbed, arable, temperate regions of the earth. These invasions have resulted in considerable economic and environmental costs. The success of the Setaria spp.-gp is because of their intimate evolutionary relationship with humans, disturbance, agriculture, and land management. The ability to adapt rapidly to local conditions is the hallmark of this weedy group. Genotypic and phenotypic biodiversity provides this spp.-gp with traits that allow it to invade, colonize, adapt to, and endure in a wide range of habitats around the world. The phenotypic life-history traits important to the success of weedy Setaria spp. begin with the induction of dormancy in seed during embryogenesis. The formation of long-lived, heterogeneous seed pools in the soil is the inevitable consequence of the dormant seed rain. In soil seed pools, after-ripening, the occurrence and timing of seedling emergence, and the induction of secondary (summer) dormancy are regulated by seasonally and diurnally varying soil oxygen, water, and temperature signals. Precise and variable timing of seedling emergence ensures Setaria a dominant place in disturbed and managed communities during the growth and reproductive phases that follow. Once established in a community, phenotypic plasticity inherent in an individual weedy Setaria sp. allows it to maximize its growth, form, and reproduction to the specific local conditions it encounters, including competitive interactions with neighbors. Traits controlling the plastic development of plant architecture include the ability to form one or more tillering shoots whose stature and number are precisely sized to local conditions. A complex pattern of branching, from plant to spikelet, provides diverse microenvironments within which different levels of dormancy are induced in individual seeds on a panicle and among panicles on a common plant. Traits for adaptation to stress in weedy Setaria spp. include tolerance to many inhibitory chemicals (e.g., herbicides, salt), mechanical damage, and drought. Genetic traits such as self-pollination and small genome size contribute to a highly diverse collection of locally adapted genotypes and phenotypes ready to exploit any opportunities provided by a cropping system. Self-pollinating Setaria spp. exist in wild, weed, and crop variants, an ideal genetic condition ensuring both long-term stability and novelty. Weedy Setaria spp. populations have low to exceedingly low amounts of total genetic variation, unusually low intrapopulation genetic diversity, and unusually high genetic diversity between populations compared with an average plant species. These traits result spatially in local populations that are unusually homogeneous, typically consisting of a single multilocus genotype. Either a generally or a specifically adapted genotype of an individual species might predominate in that local population. Across the landscape, different single-genotype populations dominate particular local sites, providing novel genetics to the region by dispersal and gene flow when conditions change. Across North America, populations of green foxtail and knotroot foxtail are genetically differentiated along a north–south gradient. The history of invasion and colonization, the successful life histories of locally adapted weedy Setaria spp., and the evolutionary potential of this weed group emphasize the need for accurate prediction of its behavior. Weedy Setaria spp. management is the management of local selection pressure and consequent adaptation. Farmers, land managers, policy makers and regulators, homeowners, and consumers need accurate information about weedy Setaria spp. to predict and guide management decisions based on economics, risk, and environmental sustainability.