This review examines the effects of n-3 fatty acids on serum lipid and lipoprotein concentrations in seven species of experimental animals. n-3 Fatty acids consistently lower serum triacylglycerol concentrations in humans but not in most animals. In addition, a common effect of n-3 fatty acids in animals is a marked reduction in high-density-lipoprotein-cholesterol concentrations, a response virtually never seen with fish-oil supplementation in humans. These differences between animals and humans arise not only from underlying species differences in lipoprotein metabolism but also from differences in experimental designs, the most notable of which is the tendency to feed animals much larger amounts of n-3 fatty acids than supplements provide for humans. Thus, great care must be taken not only to use appropriate animal models when studying lipoprotein metabolism but also to feed the animals comparable amounts of n-3 fatty acids. Failure to properly address these issues will make it difficult to uncover the biochemical basis for the hypolipidemic effect of fish oils in humans through use of experimental animals.