During adolescence, individuals experience a broad range of dynamic environments as they strive to establish independence. Learning to respond appropriately in both new and previously encountered environments requires that an individual identify and learn the meaning of cues indicating that a behavior is appropriate, or alternatively, that it should be altered or inhibited. Although the ability to regulate goal-directed behavior continues to develop across adolescence, the specific circumstances under which adolescents experience difficulty with inhibitory control remain unclear. Here we review recent findings in our laboratory that address how adolescents learn to proactively inhibit a response. Much of our research has utilized a negative occasion setting paradigm, in which one cue (a feature) gates the meaning of a second cue (a target). The feature provides information that resolves the ambiguity of the target and indicates the appropriate behavioral response to the target. As such, we have been able to determine how adolescents learn about ambiguous stimuli, such as those whose meaning changes in accordance with other features of the surrounding environment. We consider why adolescents in particular exhibit difficulty in negative occasion setting compared to either pre-adolescents or adults. In addition, we review findings indicating that a balance between orbitofrontal cortex and nucleus accumbens is necessary to support normal negative occasion setting. Finally, we consider aspects of associative learning that may contribute to adolescent inhibitory control, as well as provide insight into adolescent behavior as a whole.