Although an overwhelmingly large portion of the resources in toxicologic research is devoted to single chemical studies, the toxicology of chemical mixtures, not single chemicals, is the real issue regarding health effects of environmental and/or occupational exposure to chemicals. The relative lack of activities in the area of toxicology of chemical mixtures does not suggest ignorance of the importance of the issue by the toxicology community. Instead, it is a reflection of the difficulty, complexity, and controversy surrounding this area of research. Until recently, much of the literature on the toxicology of chemical mixtures has been either very focused on certain specific interaction studies or slanted toward broad-based, relatively vague theoretical deliberation. The typical interaction study involved binary mixtures at relatively high dose levels with acute toxicities as endpoints. Although the theoretical papers have been valuable contributions, little is available on actual, practical experimental approaches toward a systematic solution of this immensely complex area of research. We present here a broad discussion on the important issues of the toxicology of chemical mixtures. First, we provide some background information with respect to the problem and significance of toxicology of chemical mixtures in relation to some of the real life issues. Second, we review and compare the existing experimental approaches relevant to toxicologic interactions of chemical mixtures. Third, we propose three integrated approaches that involve the combination of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with: (1) Monte Carlo simulation, (2) median effect principle (MEP), and (3) response surface methodology (RSM). These modeling approaches, coupled with very focused mechanistically based toxicology studies, could be the basis for solving the problems of toxicology and risk assessment of chemical mixtures.