Examining the influence of environmental exposures on various health indices is a critical component of the planned National Children’s Study (NCS). An ideal strategy for the exposure monitoring component of the NCS is to measure indoor and outdoor concentrations and personal exposures of children to a variety of pollutants, including ambient particulate and gaseous pollutants, biologic agents, persistent organics, nonpersistent organics (e.g., pesticides), inorganic chemicals (e.g., metals), and others. However, because of the large sample size of the study (~ 100,000 children), it is not feasible to assess every possible exposure of each child. We envision that cost-effective strategies for gathering the necessary exposure-related information with minimum burden to participants, such as broad administration of product-use questionnaires and diaries, would likely be considered in designing the exposure component of the NCS. In general a biologic (e.g., blood, urine, hair, saliva) measure could be the dosimeter of choice for many of the persistent and for some of the nonpersistent organic pollutants. Biologic specimens, such as blood, can also indicate long-term internal dose to various metals, including lead and mercury. Environmental measures, on the other hand, provide pathway/source-specific exposure estimates to many of the environmental agents, including those where biologic measurements are not currently feasible (e.g., for particulate matter and for some gaseous criteria pollutants). However, these may be burdensome and costly to either collect or analyze and may not actually indicate the absorbed dose. Thus, an important technical and logistical challenge for the NCS is to develop an appropriate study design with adequate statistical power that will permit detection of exposure-related health effects, based on an optimum set of exposure measurement methods. We anticipate that low-cost, low-burden methods such as questionnaires and screening type assessments of environmental and biologic samples could be employed, when exposures at different critical life stages of vulnerability can be reliably estimated by these simpler methods. However, when reliability and statistical power considerations dictate the need for collecting more specific exposure information, more extensive environmental, biologic, and personal exposure measurements should be obtained from various “validation” subsets of the NCS population that include children who are in different life stages. This strategy of differential exposure measurement design may allow the exposure–response relationships to be tested on the whole cohort by incorporating the information on the relationship between different types of exposure measures (i.e., ranging from simple to more complex) derived from the detailed validation subsamples.