To survive and reproduce, an individual organism must accomplish goals like foraging for food and finding mates in spite of changing and threatening environments. Successful goal-directed behavior requires identification of the goal and a behavioral strategy to achieve it, initiation of behavior toward the goal, sustained execution of behavior until the goal has been completed, and adaptive termination of such behavior when it is no longer worthwhile. Here, I have examined the role of the medial prefrontal cortex (mPFC) projection to the ventral tegmental area (VTA) in the initiation of goal-directed behaviors, and the lateral habenula (LHb) in its adaptive termination in mice. First, using fiber photometry to measure population calcium activity, I show that mPFC-VTA activity increases upon the switch away from one behavior to the initiation of the next, including as mice shift from reward consumption to reward seeking in an operant task and from immobility to mobility in the tail suspension test. Importantly, mPFC-VTA activity is not modulated upon the initiation of movement that is not directed toward a goal. Similarly, mPFC-VTA optogenetic stimulation induces struggling on the tail suspension test and directs behavior toward spatial locations associated with reward, in addition to increasing movement in neutral environments. Collectively, these results suggest that mPFC-VTA activity signals and is sufficient for the initiation of goal-directed behavior. Second, I demonstrate that LHb population calcium activity tonically increases as mice disengage from an operant reward task, both due to satiety and due to the denial of reward, and that this increase is independent of underlying phasic activity. Further, inhibiting LHb after the mouse disengages from the operant task does not elicit re-engagement in the goal-directed behavior, but inhibition upon re-engagement prolongs the duration for which the mouse is engaged in the task, suggesting that LHb affects the persistence of goal-directed behavior and may function as an adaptive “stop” signal. Taken together, this research provides a neural model for the initiation and adaptive termination of goal-directed behavior, and has implications for psychiatric conditions such as depression in which motivation is attenuated.