It is now well-recognized that human environmental exposures are not to single chemicals. Rather, humans are exposed, either concurrently or sequentially, to multiple chemicals. Challenges that chemical mixtures pose for risk assessment and toxicology are presented. Challenge areas include increasing the peer-reviewed publication of human studies, improving access to peer-reviewed data and examining multiple target organs. Two difficult challenges are development of a common, consistent language and the use of appropriate and innovative experimental designs and analyses. The challenge of elucidation of mechanism(s) offers a rational basis for extrapolation across dose levels, exposure durations and exposure routes as well as to other species and to other similar chemicals. Of particular importance is focusing effort on those areas of investigation where answers have the greatest potential for reducing uncertainty in risk assessments for chemical mixtures and on those chemical mixtures and multiple chemical exposures that have the greatest potential impact on human health. A particularly fruitful area for future investigation is determination of the likelihood of nonadditive interactions in humans exposed to multiple chemicals at environmental exposure levels.