The social and physical environments have long since been recognized as important determinants of health. People in urban settings are exposed to a variety of health hazards that are interconnected with their health effects. The Millennium Development Goals (MDGs) have underlined the multidimensional nature of poverty and the connections between health and social conditions and present an opportunity to move beyond narrow sectoral interventions and to develop comprehensive social responses and participatory processes that address the root causes of health inequity. Considering the complexity and magnitude of health, poverty, and environmental issues in cities, it is clear that improvements in health and health equity demand not only changes in the physical and social environment of cities, but also an integrated approach that takes into account the wider socioeconomic and contextual factors affecting health. Integrated or multilevel approaches should address not only the immediate, but also the underlying and particularly the fundamental causes at societal level of related health issues. The political and legal organization of the policy-making process has been identified as a major determinant of urban and global health, as a result of the role it plays in creating possibilities for participation, empowerment, and its influence on the content of public policies and the distribution of scarce resources. This paper argues that it is essential to adopt a long-term multisectoral approach to address the social determinants of health in urban settings. For comprehensive approaches to address the social determinants of health effectively and at multiple levels, they need explicitly to tackle issues of participation, governance, and the politics of power, decision making, and empowerment.