Adolescence represents a highly sensitive period of mammalian neurodevelopment wherein critical synaptic and structural changes are taking place in brain regions involved in cognition, self-regulation and emotional processing. Importantly, neural circuits such as the mesocorticolimbic pathway, comprising the prefrontal cortex, sub-cortical mesolimbic dopamine system and their associated input/output centres, are particularly vulnerable to drug-related insults. Human adolescence represents a life-period wherein many individuals first begin to experiment with recreational drugs such as nicotine and cannabis, both of which are known to profoundly modulate neurochemical signalling within the mesocorticolimbic pathway and to influence both long-term and acute neuropsychiatric symptoms. While a vast body of epidemiological clinical research has highlighted the effects of adolescent exposure to drugs such as nicotine and cannabis on the developing adolescent brain, many of these studies are limited to correlative analyses and rely on retrospective self-reports from subjects, making causal interpretations difficult to discern. The use of pre-clinical animal studies can avoid these issues by allowing for precise temporal and dose-related experimental control over drug exposure during adolescence. In addition, such animal-based research has the added advantage of allowing for in-depth molecular, pharmacological, genetic and neuronal analyses of how recreational drug exposure may set up the brain for neuropsychiatric risk. This review will explore some of the advantages and disadvantages of these models, with a focus on the common, divergent and synergistic effects of adolescent nicotine and cannabis exposure on neuropsychiatric risk.