Culture in the United States can be a challenging concept to define. To try to understand the way that its forces influence substance use is complicated. In the United States, a nation formed with a complex history of intertwined cultures, there are seemingly infinite avenues to explore cultural influences of substance use, and none of them can be disentangled from a history of oppression, slavery, segregation, and disenfranchisement based on race and ethnicity. As America grapples with a history of social injustices, the consequences of substance use reflect its past. This chapter will explore the historical influences that impact incarceration disparities, intervention stigma, and public opinion related to substance use. Specifically, it will review the impact of historic drug policies, the current opioid epidemic in marginalized groups, and the consequences of alcohol use among First Nations.