This unique overview of systems toxicology methods and techniques begins with a brief account of systems thinking in biology over the last century. We discuss how systems biology and toxicology continue to leverage advances in computational modeling, informatics, large-scale computing, and biotechnology. Next, we chart the genesis of systems toxicology from previous work in physiologically based models, models of early development, and more recently, molecular systems biology. For readers interested in further details this background provides useful linkages to the relevant literature. It also lays the foundations for new ideas in systems toxicology that could translate laboratory measurements of molecular responses from xenobiotic perturbations to adverse organ level effects in humans. By providing innovative solutions across disciplinary boundaries and highlighting key scientific gaps, we believe this chapter provides useful information about the current state, and valuable insight about future directions in systems toxicity.