Voluntary job separation, or quitting, occurs for a variety of reasons. Although it is often a positive move, it may also lead to periods of unemployment. Studies suggest that one factor that may be implicated in the likelihood of quitting is illicit drug use: Adult drug users may not only quit more frequently but also have a heightened probability of unemployment following a quit. Yet, prior research has not taken a sufficient longitudinal perspective, considered contemporary research on job mobility, nor examined gender differences. We assessed the association using longitudinal data on 8,512 individuals followed from 1984 to 1995. The results indicated that marijuana and cocaine use were associated with a higher probability of quitting. Moreover, marijuana use among males, but not females, was associated with a higher likelihood of experiencing periods of unemployment following a quit. We discuss the implications of these results for understanding gender-distinct patterns of drug use and occupational trajectories.