More lesbian, gay, and bisexual (LGB) youths than heterosexuals report substance use. We examined a theoretical model to understand these disparities in lifetime and past-year substance use by means of stress and attachment paradigms, using the longitudinal Growing Up Today Study (GUTS) and Nurses’ Health Study II (NHSII). GUTS participants are the children of participants in NHSII; thus, child and maternal data are available. In addition, GUTS contains siblings, allowing for comparisons of LGB and heterosexual siblings. Of 5,647 GUTS youths (M = 20.6 years old in 2005), 1.6% were lesbian/gay (LG), 1.6% bisexual (BI), 9.9% mostly heterosexual (MH), and 86.9% completely heterosexual (CH). After adjusting for sibling clustering in GUTS and covariates, significantly more sexual minorities (LGs, BIs, and MHs) than CHs reported lifetime and past-year smoking, nonmarijuana illicit drug use, and prescription drug misuse. More sexual minorities also reported marijuana use in the past year. The relations between sexual orientation and substance use were moderated by the stress markers: As mother’s discomfort with homosexuality increased, more BIs and MHs than CHs used substances. As childhood gender nonconforming behaviors increased, more LGs than CHs used substances. The relations between sexual orientation and substance use were mediated by attachment and maternal affection (percent of effect mediated ranged from 5.6% to 16.8%% for lifetime substance use and 4.9% to 24.5% for past-year use). In addition, sibling comparisons found that sexual minorities reported more substance use, more childhood gender nonconforming behaviors, and less secure attachment than CH siblings; mothers reported less affection for their sexual minority than CH offspring. The findings indicate the importance of stress and attachment paradigms for understanding sexual-orientation disparities in substance use.