Chronic pain is pain that persists for 3 or more months, often without discernible cause. There are many risk factors associated with chronified pain, including cognitive dysfunction and substance use. This dissertation uses multiple genetically informed methods to examine questions about genetic and environmental influences on chronic pain and its risk factors. Overall, these studies examine the phenotypic, genetic, environmental, and epigenetic relationships of chronic pain with executive functions and substance use. Study I found that chronic pain in young adults specifically relates to updating working memory, rather than to common executive function or mental set shifting, and that the association was entirely due to genetic effects. Study II demonstrates that the relationship between chronic pain and smoking may be due to underlying genetic risk, rather than a direct relationship, and that the reward pathway in the brain does not appear to be a significant mediator of the association. Study III shows that general chronic pain risk genetically relates to substance use disorder risk, and also shares additional associations with cigarette consumption and alcohol frequency. This dissertation establishes the importance of using genetically informed methods to interrogate epidemiological questions of interest.