Health risk behaviors shape, and are shaped by, the people with whom we interact throughout our lives. The use of substances, including alcohol or narcotics, is one such behavior, yet it is often empirically examined in isolation of other people. As such, it has been repeatedly shown that excessive alcohol consumption, illicit drug use, and the extra-medical use of prescription narcotics are, collectively, a leading cause of preventable injury, severe illness, and premature death. However, by not considering that substance use which leads to harms (hereafter, substance misuse) is inseparable from social contexts, the burden of substance misuse may be greatly underestimated. Drawing on a Swedish birth cohort from 1953, and centered on the concept of interdependent—linked—lives, this thesis encompasses four empirical studies of social relationships and substance misuse. Each study examines the association between substance misuse and friends and parents, siblings, spouses, and offspring, respectively. Study I explored whether childhood adversity in two contexts, within the family of origin and among one’s adolescent friends at age 13, was a potential risk factor for later substance misuse. The study found independent associations between substance misuse and childhood adversity in both contexts. Study II estimated differences in substance misuse between siblings in midlife according to birth order, and showed that substance misuse during this life course period may be better explained by factors within the family of origin. Study III examined the effects of substance misuse on nearly 50 years of marital status transitions. The results suggest that a lifetime history of substance misuse affects marital status transitions, and that substance misuse may increase the risk of marital dissolution. Finally, in investigating changes in parental psychotropic medication use in relation to their offspring’s hospitalization for substance misuse, Study IV demonstrated that such stressful life events as an offspring’s hospitalization for narcotics use may have a detrimental impact on maternal mental health. The findings from the thesis underscore that factors within the families of both origin and destination have the potential to affect, and be affected by, substance misuse throughout the life course. The thesis concludes substance misuse neither starts, nor ends, with the individual. Accordingly, public health efforts could benefit from approaching substance misuse from the perspective of linked lives.