Harbor seals are exposed to increasing pressure caused by anthropogenic activities in their marine environment. Persistent organic pollutants (POPs) and trace elements are hazardous contaminants that accumulate in tissues of harbor seals. POPs and trace elements can negatively affect the immune-system and have been reported, e.g., to increase susceptibility to viral infections in seals. Biomarkers of the xenobiotic metabolism, cytokines, and heat-shock protein as cell mediators of the immune-system were established to evaluate the impact of environmental stressors on harbor seals. Harbor seals (n = 54) were captured on sandbanks in the North Sea during 2009-2012. Health assessments, including hematology, were performed, and RNAlater blood samples were taken and analyzed using quantitative polymerase chain reaction. Normalized transcript copy numbers were correlated to hematology and POP concentration in blood and trace metals in blood and fur. A significant correlation between xenobiotic markers and contaminant burden was found. Significant interrelationships between markers and POP compounds, as well as with season, weight, and hematology values, indicate that biomarkers reflect pollutant exposure and effects. A significant relationship between cortisol levels and heat-shock protein expression was observed indicating stress experienced during restraint of the seals. Interleukin-10 transcription showed significant correlations with trace elements in fur pointing toward immune regulatory effects of metal exposure. The molecular markers prove to be an important noninvasive tool that reflects contaminant exposure and the impact of anthropogenic stressors in seal species. The connection between interleukin-2, xenobiotic markers, and pollutants may indicate immune suppression in animals exposed to contaminants with subsequent susceptibility to inflammatory disease.