Dramatic increases in opioid and drug overdose mortality have occurred in the United States (US) over the past two decades. To address this national public health crisis and identify gaps in the literature, we analyzed recent empirical trends in US drug overdose mortality by key social determinants and conducted a selective review of the recent literature on the magnitude of the opioid crisis facing different racial/ethnic, socioeconomic, and rural-urban segments of the US population.We used the 1999-2017 mortality data from the US National Vital Statistics System to analyze trends in drug overdose mortality by race/ethnicity, age, and geographic area. Log-linear regression was used to model mortality trends. Using various key words and their combinations, we searched PubMed and Google Scholar for select peer-reviewed journal articles and government reports published on the opioid epidemic between 2010 and 2018.Our original analysis and review indicate marked increases in drug overdose mortality overall and by race/ethnicity and geographic regions, with adolescents and young adults experiencing steep increases in mortality between 1999 and 2017. Our selective search yielded 405 articles, of which 39 publications were selected for detailed review. Suicide mortality from drug overdose among teens aged 12-19 increased consistently between 2009 and 2017, particularly among teen girls. The rise of efficient global supply chains has increased opioid prescription use and undoubtedly contributed to the opioid epidemic. Many other important contributing factors to the epidemic include lack of education and economic opportunities, poor working conditions, and low social capital in disadvantaged communities.Our analysis and review indicate substantial disparities in drug overdoses and related mortality, pain management, and treatment outcomes according to social determinants. Increases in drug overdoses and resultant mortality are not only unique to the US, but have also been observed in other industrialized countries. Healthcare systems, community leaders, and policymakers addressing the opioid epidemic should focus on upstream structural factors including education, economic opportunity, social cohesion, racial/ethnic disadvantage, geographic isolation, and life satisfaction.