The US Environmental Protection Agency is engaged in the development of risk assessment guidelines and methodologies as part of the regulatory program of the Agency. The primary goal of the Agency was originally to accurately assess the effects of human exposure to single chemicals in a single medium (e.g. water) over a human lifetime. Assessment methods for estimating low-dose lifetime cancer risk for known or suspected human carcinogens, or long-term acceptable daily intake (ADI) levels for threshold-acting toxicants, were developed and successfully applied to meet this need. Now there is an increasing need for methods which address more complex exposure situations, including multichemical, multiroute, and partial-lifetime exposures. Improvements in the current methods are also needed. Several issues now under study are briefly described.