Using two waves of data from a national survey of working Americans (N = 1,122), we examine the associations among economic hardship, negative life events, and psychological distress in the context of the family-work interface. Our findings demonstrate that family-to-work conflict mediates the effects of economic hardship and negative events to significant others on distress (net of baseline distress and hardship). Moreover, economic hardship and negative events to significant others moderate the association between family-to-work conflict and distress. While negative events to others exacerbate the positive effect of family-to-work conflict on distress, we find the opposite for economic hardship: The positive association between hardship and distress is weaker at higher levels of family-to-work conflict. These patterns hold across an array of family, work, and sociodemographic conditions. We discuss how these findings refine and extend ideas of the stress process model, including complex predictions related to processes of stress-buffering, resource substitution, and role multiplication.