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This article provides a selected overview of 20 years of research on the role of psychosocial factors in susceptibility to upper respiratory infections. We present evidence from our laboratory that psychological stress is associated with increased risk for developing respiratory illness for persons intentionally exposed to a common cold virus, that the longer the duration of the stressor the greater the risk, and that stress association with susceptibility may be mediated by stress-induced disruption of the regulation of proinflammatory cytokines. We further provide evidence that social relationships (social integration and social support) are also associated with risk for respiratory illness: Social integration is associated with reduced risk irrespective of stress level and social support protects persons from the pathogenic influences of stress. Finally, we report recent evidence that lower levels of early childhood socio-economic status (SES) are associated with greater risk of viral-induced illness during adulthood, independent of adult SES.