Widespread observations of organic compounds in vegetation, soil, animals, and human tissue have motivated research on more accurate characterizations of chemical transport over regional, continental, and global scales. Efforts to assess human and ecosystem exposure to contaminants from multiple environmental media have been evolving over the last several decades. In this review we summarize the development and evolution of the multimedia mass-balance approach to pollutant fate and exposure evaluation and illustrate some of the calculations used in multimedia assessments. We describe the concepts that make possible the Mackay-type mass-balance compartment models. We describe ongoing efforts to use multimedia models to quantify human exposures. We use a series of case studies of varying complexity to illustrate capabilities and limitations of selected multimedia approaches. We look to the future and consider current challenges and opportunities in the field of multimedia contaminant fate and exposure modeling.