A full understanding of the role of the urban environment in shaping the health of populations requires consideration of different features of the urban environment that may influence population health. The social environment is key to understanding the way in which cities affect the health of populations. Social determinants of health (SDH) are important, generally, yet can have different effects in different settings from urban to rural, between countries, between cities, and within cities. Failure to acknowledge, and more importantly, to understand the role of SDH in health and access to health and social services will hamper any effort to improve the health of the population. In this paper, we will briefly summarize a few key SDH and their measurement. We will also consider methodologic tools and some methodologic challenges. The concepts presented here are broadly applicable to a variety of settings: developed and developing countries, slum areas, inner cities, middle income neighborhoods, and even higher income neighborhoods. However, our focus will be on some of the more vulnerable urban populations who are most profoundly affected by SDH.