BACKGROUND: We draw on a relational theoretical perspective to investigate how the social division and structure of labor are associated with serious and moderate mental illness and binge and heavy drinking. METHODS: The Panel Study of Income Dynamics and the Occupational Information Network were linked to explore how occupation, the productivity-to-pay gap, unemployment, the gendered division of domestic labor, and factor-analytic and theory-derived dimensions of work are related to mental illness and drinking outcomes. RESULTS: Occupations involving manual labor and customer interaction, entertainment, sales, or other service-oriented labor were associated with increased odds of mental illness and drinking outcomes. Looking for work, more hours of housework, and a higher productivity-to-pay gap were associated with increased odds of mental illness. Physical/risky work was associated with binge and heavy drinking and serious mental illness; technical/craft work and automation were associated with binge drinking. Work characterized by higher authority, autonomy, and expertise was associated with lower odds of mental illness and drinking outcomes. CONCLUSIONS: Situating work-related risk factors within their material context can help us better understand them as determinants of mental illness and identify appropriate targets for social change.