This issue of Current Opinion in Toxicology presents thirteen articles reviewing the state of the science in risk assessment of chemicals. The development of new approach methods (NAMs; including in vitro and in silico techniques) is the key to addressing specific drawbacks in traditional animal-based toxicology testing, namely, low throughput, and the difficulty of directly assessing toxicity mechanisms. The articles by Hornberg, Harrill, Grapel, Becker, and Pham address new in vitro and in silico methodologies and accompanying challenges in using these NAMs in chemical risk assessment. One well-known issue with the use of in vitro methods is the need to connect cell-level data to predictions of effects at the whole-organism level. Articles by Piersma, Brunak, Saili, and Licht address this issue demonstrating the use of integrative or systems-level modeling. A parallel throughput challenge is the assessment of exposures for thousands of chemicals in the environment and the use of this information in quantitative risk assessments. Wambaugh, Johansson, and Boberg address various aspects of exposure, which are high-throughput prediction of exposures, the use of existing human biomonitoring (HBM) data in the context of risk assessment, and simultaneous exposure to many chemicals at the same time (mixture effects). A final challenge addressed in this issue is the acceptance of these NAMs as an input to regulatory decision-making, which is the topic discussed by Browne.