Few studies have examined the socio-cultural determinants of alcohol and drug misuse trajectories among adult Latinas. To assess the associations between socio-cultural determinants and alcohol and drug misuse, we used a longitudinal design to follow a sample of adult Latina mother-daughter-dyads (N = 267) for ten years, and collected four waves of data. They were adult Latinas of Caribbean, South and Central American descent. Specifically, this study investigated the effects of the following factors: (1) Individual Determinants (e.g., socioeconomic conditions, mental health, and medical status); (2) Cultural Determinants (e.g., acculturation to US culture); (3) Interpersonal Determinants (e.g., interpersonal support, relationship stress, mother-daughter attachment, intimate partner violence); (4) Community Determinants (e.g., neighborhood related stress); and (5) Institutional Determinants (e.g., religious involvement, involvement with the criminal justice system). Using hierarchical modeling, we found that taking prescribed medication on a regular basis for a physical problem, religious involvement, and mother-daughter attachment were negatively associated with drug misuse, while involvement in criminal activity was positively associated with drug misuse. Regarding alcohol misuse, results showed that age at arrival in the United States, number of years in the United States, and religious involvement were negatively associated with alcohol misuse, while involvement in criminal activity was positively associated with alcohol misuse. Based on our findings, explicit implications are provided for culturally relevant interventions.