Employer initiatives that address the spillover of work strain onto family life include flexible work schedules. This study explored the mediating role of negative work-family spillover in the relationship between schedule flexibility and employee stress and the moderating roles of gender, family workload, and single-parent status. Data were drawn from the 2008 National Study of the Changing Workforce, a nationally representative sample of working adults (N = 2,769). The results indicated that schedule flexibility was associated with less employee stress and that these associations were mediated by perceptions of negative work-family spillover. This study found the moderating relationships of gender, family workload, and single parenting in the relationships between schedule flexibility and negative work-family spillover and stress. Schedule flexibility had stronger relationships in reducing negative work-family spillover and stress among women, single parents, and employees with heavier family workloads. The findings provide empirical support for intervention efforts involving schedule flexibility to reduce workplace stress among employees with family responsibilities. (Contains 4 tables, 5 figures, and 1 note.)