Salivary cortisol measures are increasingly being incorporated into large-scale, population-based, or epidemiological research, in which participants are selected to be representative of particular communities or populations of interest, and sample sizes are in the order of hundreds to tens of thousands of participants. These approaches to studying salivary cortisol provide important advantages but pose a set of challenges. The representative nature of sampling, and large samples sizes associated with population-based research offer high generalizability and power, and the ability to examine cortisol functioning in relation to: (a) a wide range of social environments; (b) a diverse array individuals and groups; and (c) a broad set of pre-disease and disease outcomes. The greater importance of high response rates (to maintain generalizability) and higher costs associated with this type of large-scale research, however, requires special adaptations of existing ambulatory cortisol protocols. These include: using the most efficient sample collection protocol possible that still adequately address the specific cortisol-related questions at hand, and ensuring the highest possible response and compliance rates among those individuals invited to participate. Examples of choices made, response rates obtained, and examples of results obtained from existing epidemiological cortisol studies are offered, as are suggestions for the modeling and interpretation of salivary cortisol data obtained in large-scale epidemiological research.