Nutraceuticals are food constituents with potential health benefits beyond their nutritional value. In vitro and in vivo studies suggest a protective effect of nutraceuticals against chronic diseases, but the results are not supported fully by clinical evidence. From a toxicological perspective, nutraceuticals are recognized generally as safe at dietary doses; however, they are often consumed at higher doses in the form of nutritional supplements. Exposure to supra-dietary doses of nutraceuticals is of toxicological concern, particularly because some substances may cause genomic changes in target tissues. This chapter describes a systems biology-based approach for the toxicological assessment of nutraceuticals that uses computable mechanistic network models to identify and quantify molecular pathways perturbed upon exposure to high doses of nutraceuticals. This chapter also provides specific examples of how microarray-based transcriptome analyses and high-content screening methods can be applied to evaluate the biological impacts of resveratrol, quercetin, astaxanthin, and epigallocatechin gallate in human cryopreserved hepatocytes and coronary artery endothelial cells.