The first of the 2014 Loebel Lectures in Philosophy and Psychiatry, by Professor Kenneth S Kendler I show how recent studies in the genetic epidemiology and molecular genetics of psychiatric and substance use disorders illustrate the complex causal pathways to mental illness. These include gene-environment interaction in the etiology of major depression (MD) and substance use and abuse, gene-social interactions in drug use, environment-environment interaction in the etiology of MD, and gene-environment covariation in the etiology of MD. I will illustrate the role of genetic factors on the comorbidity of psychiatric disorders using both twin and molecular methods, and describe complex developmental models for MD and alcohol use disorder. I will conclude with a classical example of top-down causation: the impact of human decision-making on the gene-to-phenotype pathway for psychiatric illness.