Substance use and substance use disorders (SUDs) have been linked with marital discord. Relatively little is known, however, about the antecedents of SUDs, the mediators of these factors over time, or their associations with the spousal/partner relationship among urban adults. A better understanding of the longitudinal pathways to marital conflict and to SUDs should help prevention and intervention programs target their precursors within the developmental period in which they occur. The present study, therefore, examined the longitudinal predictors of an unsupportive spousal/partner relationship and SUDs among a community sample of urban African American and Puerto Rican adults from East Harlem, NY. Participants (N = 816) completed structured questionnaires at five time waves, from adolescence to adulthood (mean ages = 14, 19, 24, 29, and 32 years). Structural equation modeling examined the effects of earlier environmental and social stressors and intrapersonal and interpersonal factors on later SUDs in adulthood. There was a good fit of the structural equation model (CFI = 0.91; RMSEA = 0.06; and SRMR = 0.06), which revealed three main pathways from adolescence to the spousal/partner relationship and SUDs in adulthood. One pathway linked a weak parent-adolescent attachment relationship with the participant's psychological symptoms in emerging adulthood (p < 0.01), which in turn were related to affiliation with deviant and drug-using peers, also in emerging adulthood (p < 0.001). Peer deviance and drug use were associated with the participant's substance use in young adulthood (p < 0.001), which predicted both an unsupportive spousal/partner relationship (p < 0.05) and SUDs (p < 0.001) later in adulthood. Other pathways highlighted the continuity of psychological symptoms as related to both substance use in young adulthood (p < 0.001) and an unsupportive spousal/partner relationship in adulthood (p < 0.001). Findings showed that the associations of both distal stressors and the parent-adolescent relationship with more proximal intra- and interpersonal problems predicted unsupportive spousal/partner relationships and SUDs among urban adults. Several aspects of the individual's life, at different developmental stages, provide opportunities for interventions to prevent or reduce unsupportive spousal/partner relationships and SUDs.