The field of toxicology is on the cusp of a major transformation in how the safety and hazard of chemicals are evaluated for potential effects on human health and the environment. Brought on by the recognition of the limitations of the current paradigm in terms of cost, time, and throughput, combined with the ever increasing power of modern biological tools to probe mechanisms of chemical-biological interactions at finer and finer resolutions, 21st century toxicology is rapidly taking shape. A key element of the new approach is a focus on the molecular and cellular pathways that are the targets of chemical interactions. By understanding toxicity in this manner, we begin to learn how chemicals cause toxicity, as opposed to merely what diseases or health effects they might cause. This deeper understanding leads to increasing confidence in identifying which populations might be at risk, significant susceptibility factors, and key influences on the shape of the dose-response curve. The U. S. Environmental Protection Agency (EPA) initiated the ToxCast, or "toxicity forecaster", program 5 years ago to gain understanding of the strengths and limitations of the new approach by starting to test relatively large numbers (hundreds) of chemicals against an equally large number of biological assays. Using computational approaches, the EPA is building decision support tools based on ToxCast in vitro screening results to help prioritize chemicals for further investigation, as well as developing predictive models for a number of health outcomes. This perspective provides a summary of the initial, proof of concept, Phase I of ToxCast that has laid the groundwork for the next phases and future directions of the program.