Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of American Association for the Advancement of Science for personal use, not for redistribution. The definitive version was published in Science 354 (2016): 1305-1308, doi:10.1126/science.aah4993. ; Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl hydrocarbon receptor-based signaling pathway as a shared target of selection. This suggests evolutionary constraint on adaptive solutions to complex toxicant mixtures at each site. However, distinct molecular variants apparently contribute to adaptive pathway modification among tolerant populations. Selection also targets other toxicity-mediating genes, and genes of connected signaling pathways, indicating complex tolerance phenotypes and potentially compensatory adaptations. Molecular changes are consistent with selection on standing genetic variation. In killifish high nucleotide diversity has likely been a crucial substrate for selective sweeps to propel rapid adaptation. ; Primary support was from the United States National Science Foundation (collaborative research grants DEB-1265282, DEB-1120512, DEB- 1120013, DEB-1120263, DEB-1120333, DEB-1120398 to JKC, DLC, MEH, SIK, MFO, JRS, WW, and AW). Further support was provided by the National Institutes of Environmental Health Sciences (1R01ES021934-01 to AW; P42ES007381 to MEH; R01ES019324 to JRS), and the National Science Foundation (OCE-1314567 to AW). BC was supported by the Postdoctoral Research Program at the US EPA administered by the Oak Ridge Institute for Science and Education (Agreement DW92429801).