This study investigated sub-lethal effects and detoxification processes activated in free-ranging Red Knots (Calidris canutus) from the Pertuis Charentais on the Atlantic coast of France, and compared the results with previous data obtained on another shorebird species, the Black-tailed Godwit (Limosa limosa). The concentrations of 13 trace elements (Ag, As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, Zn) were assessed in the liver, kidneys, muscle and feathers. Stable isotope analyses of carbon and nitrogen were carried out to determine whether differences in diet explained variations in elemental uptake. The mRNA expression of relevant genes (cytochrome c oxidase 1, acetyl-CoA carboxylase, superoxide dismutase Cu/Zn and Mn, catalase, metallothionein, malic enzyme), antioxidant enzyme activities (catalase, glutathione peroxidase (GPx), superoxide dismutase), and metallothionein (MT) levels were investigated to shed light on trace element detoxification and toxic effects. Although Red Knots were characterized by elevated As and Se concentrations which were potentially toxic, most elements were usually below toxicity threshold levels. The results strongly suggested a dietary specialization of Red Knots, with individuals feeding on higher trophic status prey experiencing higher As, Hg and Se burdens. Red knots and Godwits also showed discrepancies in elemental accumulation and detoxification processes. Higher As and Se concentrations in Red Knots enhanced catalase gene expression and enzyme activity, while Godwits had higher Ag, Cu, Fe and Zn levels and showed higher MT production and GPx activity. The results strongly suggest that detoxification pathways are essentially trace element- and species-specific.