It has been widely reported that currently used biomarkers of drug toxicity lack sensitivity, specificity and a fundamental mechanistic basis. The lack of qualified mechanistic biomarkers has resulted in a significant challenge to investigate the true extent and diagnosis of ADRs. Two current organ systems that are frequent toxicology targets for marketed drugs or those in development include the liver and kidney. The currently clinical available biochemical tests used for both of these organ systems lack sensitivity and specificity. There is also increasing interest in genomic biomarkers in drug safety, with most of the advances being seen with HLA gene polymorphisms and the risk for immune-mediated diseases affecting different organ systems, most prominently the skin and liver. We will focus on all these areas in this chapter.