Polychlorinated biphenyls (PCBs) are a class of anthropogenic chemical compounds used by industry from the 1940s until the 1970s. Two General Electric plants at Fort Edward and Hudson Falls, NY contaminated the Hudson River by disposing roughly 604,500 kg of PCBs into the waterway during that time. This research focused on using whole-genome screening to find novel biochemical responses in laboratory and wild birds that are exposed to PCB mixtures relevant to the Hudson River. We used two PCB congener profiles, found in spotted sandpiper eggs and in tree swallow eggs from the Hudson River area of concern. We also tested PCB 126 and PCB 77 singly, since both have very high avian TEQs compared to other PCB congeners. Microarray technology was used to assess the spotted sandpiper mixture in Japanese quail. Pathways of interest were identified and qPCR was performed on a suite of genes to assess the response levels of Japanese quail that were exposed to both mixtures as well as the single congeners. Ethoxyresorufin-O-deethylase (EROD) was assessed in Japanese quail with all treatments, and in tree swallow and bluebird populations at the Hudson River site, and at three reference sites. Major findings from the microarray study revealed that the pathways for xenobiotic metabolism, oxidative damage, endocrine disruption, and energy balance were all impacted with PCB exposure. For the four compounds tested with both sexes, EROD activity increased in laboratory birds for seven of those eight sex/compound combinations. Cytochrome P450 1A4 and cytochrome P450 1A5 were the most consistently responsive genes for all sex/compound combinations. All other genes showed varied responses that changed with concentration, compound, and sex, however there were few differences seen at the level of significance (p<0.05). EROD exhibited mild response to PCB exposure in wild birds, with significant (p<0.05) differential expression in environmentally exposed birds at the Hudson River across years, 2006-2008. In summary, this research demonstrates that xenobiotic metabolism remains a highly responsive pathway with PCB exposure and that this pathway responds to PCB mixtures in a manner that does not mirror the toxic equivalency of the component PCBs.