Human health risks associated with changes in synthetic chemical pesticide use following the introduction of genetically modified crops are quantified in this article. Bacillus thuringiensis (Bt) cotton and herbicide-tolerant (HT) soybean, two genetically modified crops, were chosen as the focus for this study based on their global popularity.  An innovative multimedia total exposure model, CalTOX, was used to calculate the health risks for two target populations, before and after the introduction of Bt cotton and HT soybean.  Major results include the quantification of incremental lifetime cancer risk based on a time-weighted average exposure, and the quantification of hazard ratios for non-cancer effects based on the maximum exposure rate value, both computed over the exposure duration.  Results show that human health risks are not intuitively and necessarily reduced with the reduction of pesticide use.  For example, more trifluralin was used after the introduction of HT soybeans in Iowa and Minnesota, leading to higher risks.  Moreover, the general population may have larger exposures to pesticides when compared with the population living in areas where pesticides are actually applied.  This may occur because exposure to pesticides is not only dependent on geographical distance from the contaminated area, but also strongly dependent on other factors, such as the characteristic travel distance and environmental persistence.