Abstract The present study examined the available literature linking whole-body tissue concentrations with toxic effects in fish species for copper and cadmium. The variability in effect concentration for both copper and cadmium among species occurred within an order of magnitude for all responses, whereas the range for lethal toxicity based on water exposure spanned approximately 4 to 5 orders of magnitude. Fish tissue concentrations causing adverse effects were just above background concentrations, occurring between 1 μg/g and 10 μg/g for copper and 0.1 μg/g to 4 μg/g for cadmium. The results also show that salmonids are especially sensitive to cadmium, which appears to be a function of chemical potency. No studies were found that indicated adverse effects without increases in whole-body concentration of these metals. This narrow range for dose-response implies that a toxicological spillover point occurs when the detoxification capacity of various tissues within the animal are exceeded, and this likely occurs at a similar whole-body concentration for all naïvely exposed fish species. Elevated whole-body concentrations in fish from the field may be indicative of possible acclimation to metals that may or may not result in effects for target species. Acclimation concentrations may be useful in that they signal excessive metal concentrations in water, sediment, or prey species for a given site and indicate likely toxic effects for species unable to acclimate to excess metal exposure. Using tissue residues as the dose metric for these metals provides another line of evidence for assessing impaired ecosystems and greater confidence that hazard concentrations are protective for all fish species. Environ Toxicol Chem 2015;34:1309–1319. Published 2015 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.