Over the past 10 years, genome-wide association studies (GWASs) have produced a remarkable number of discoveries that have rapidly advanced psychiatric genetics, as well as our understanding of the biology associated with psychopathology. However, while these steady but gradual insights hold promise for new conceptualizations, classifications, and therapeutics in psychiatry, they have primarily focused on one phenotype at a time. This univariate approach to genetic discovery has left our knowledge of some forms of psychopathology lagging considerably behind others. In this Dissertation, I report my findings from two large-scale multivariate GWASs of phenotypes related to substance use and serious mental illness. In both studies, I used a novel combination of transdiagnostic and dimensional approaches to genetic discovery in order to advance our understanding of molecular genetic influences on these phenotypes. My results produce novel insights into the biological correlates of these psychiatric phenomena and refine the nomological networks in which they exist.