Setaria spp. (foxtails) comprise a group of serious cosmopolitan weeds. Current control strategies for these species are flawed due to the heavy reliance on herbicide use and the associated problems. An improved weed management system can only be developed after weedy adaptation is understood, through the studies of weed population biology and physiology. Investigations of Setaria's genetic diversity, population genetic structure, and variation in herbicide resistance represent the initial steps toward this goal. Isozyme analyses indicated that, foxtails, like other introduced, self-pollinating weeds, had low genetic variation but strong population genetic differentiation. At the species level, S. geniculata (knotroot foxtail, abbreviated herein as Krft) had the greatest heterozygosity, followed by S. viridis (green foxtail, or Gnft), Sglauca (yellow foxtail, or Yeft), and S. faberii (giant foxtail, or Gift). Knotroot foxtail had the strongest population differentiation followed by Yeft and Gnft. Little isozyme polymorphism was found in Gift and no further analysis was conducted for the species. There were geographic patterns in the genetic diversity of individual species. A north-south gradient occurred to Gnft and Krft populations in North America. Yellow foxtail populations formed three distinctive clusters: Asian, European, and North American cluster. Green and Yeft populations in Iowa had greater diversity than those from the rest of North America. Such population genetic structures likely resulted from founder effects, multiple introductions, and natural selection. Some populations, sampled on various geographic scales, were genetically well differentiated. Other populations from diverse ecological environments shared identical genotypes. Phylogenetically, Gnft and foxtail millet were likely the same species and several Gnft varieties appeared to be genetically identical. A high degree of genetic similarity was also shared between Krft and Yeft. Foxtails had inter-and intraspecific variation in atrazine and metolachlor resistance. The resistance mechanisms (quantitative or qualitative) to these two herbicides may be different in yellow, green and giant foxtail. Glutathioneherbicide conjugation mediated by glutathione S-transferase was not the primary detoxification mechanism for these herbicides in these foxtail species.