This study examined predictors of employment among substance-using men and women enrolled in welfare-to-work programs. Participants were 394 welfare applicants assigned to either coordinated care management or usual care for treatment services and job training and followed up for 1 year to track employment outcomes. Common barriers to work were assessed at baseline in four key domains: disabilities, situational barriers, labor capital, and motivation. Results indicated substantial gender differences in the number and profile of work barriers. Among men, work experience and job motivation were the only significant predictors of employment; among women, multiple factors from each barrier domain predicted job acquisition even when controlling for all other significant predictors. Findings suggest that welfare-to-work programs should emphasize job training and job seeking during the early stages of welfare interventions for men and for many women.