Endocannabinoids are theorized to modulate cue-motivated behavior by amplifying dopamine release within the mesolimbic dopamine system. Here, we summarize the electrochemical studies that revealed how endocannabinoids, particularly 2-arachidonoylglycerol within the ventral tegmental area, augment cue-evoked dopamine release events into the nucleus accumbens while concurrently facilitating cue-motivated behavior. Data are initially described within the context of the classical role attributed to the mesolimbic system—promoting reward seeking. We then expand our discussion beyond simple reward-directed behaviors by discussing a potential role for endocannabinoid-mesolimbic dopamine interactions in motivational switching when reward availability is temporally delayed. Next, we describe how eCB-DA interactions promote the active avoidance of harmful stimuli through newly discovered negative reinforcement mechanisms. Finally, we conclude by describing recent studies on the development of tolerance to cannabinoid-modulation of DA-release and discussing their therapeutic implications.