Health disparities (differences in health by socioeconomic groups) are a pressing issue in our society. This article provides an overview of a multilevel approach that seeks to understand the mechanisms underlying health disparities by considering factors at the individual, family, and neighborhood levels. In addition, we describe an approach to connecting these factors to various levels of biological processes (systemic inflammation, cellular processes, and genomic pathways) that drive disease pathophysiology. In the second half of the article, we address the question of why some low-socioeconomic-status (low-SES) individuals manage to maintain good physical health. We identify naturally occurring psychosocial factors that help buffer these individuals from adverse physiological responses and pathogenic processes leading to chronic disease. What is protective for low-SES individuals is not the same as what is protective for high-SES individuals, and this needs to be taken into account in interventions aimed at reducing health disparities.