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Background: Cannabis is the most commonly used illicit drug in the United Kingdom and worldwide. It is associated with a number of negative outcomes, which includes developing Cannabis Use Disorder (CUD). Individuals who meet criteria for CUD are at heightened risk for experiencing Major Depressive Disorder (MDD), the leading cause of disability worldwide. While this association has frequently been reported, the underlying mechanisms remain controversial. Aims of thesis: This thesis aims to investigate the degree of co-morbidity between lifetime rates of CUD and MDD, test whether this co-morbidity is accounted for by shared covariates, and test different twin models to investigate the sources (environmental or genetic) of and mechanisms underlying this co-morbidity. Methods: Data analysis was conducted on a sample of 3824 Australian twins and their non-twin siblings. Epidemiological analyses, using multivariable logistic regressions, tested whether CUD and MDD were significantly co-morbid in this sample, and to what extent covariates influenced this relationship. Twin models – bivariate correlated liabilities, discordant twin and co-morbidity models – examined whether the co-morbidity between the disorders could be explained by a) shared genetic and environmental factors, b) causal processes, and c) 13 different models of co-morbidity. Results: The epidemiological analyses found that MDD and CUD were significantly co-morbid in this sample: meeting diagnostic criteria for one disorder more than doubled the odds of meeting criteria for the other (odds ratio = 2.23, 95% confidence interval = 1.84–2.70). This co-morbidity could not be fully attributed to various psychiatric, trauma-related, parental, peer and demographic covariates. Bivariate twin analyses found that – when separated into genetic and environmental correlations – the only significant correlation between MDD and CUD was genetic (r =.41, 95% confidence interval = .24–.60). A possible causal relationship could not be excluded, because MDD and CUD were significantly associated (odds ratio = 2.83, 95% confidence interval = 1.12–7.19) in monozygotic twins discordant for both disorders. Co-morbidity model analyses indicated that the direction of influence was from CUD to MDD, and that CUD risk factors may cause MDD symptoms, particularly in individuals at high risk of CUD.