The current study identified alcohol and cannabis use trajectories among a sample of Mexican-origin youth and examined cultural and familial correlates from childhood to adolescence. Mexican-origin youth (N = 674) from Northern California were assessed annually from ages 10 to 17 (8 waves). Latent class growth modeling examined variability in developmental trajectories for last 3-month alcohol and cannabis use frequency. Analyses also examined between-trajectory differences in youth’s cultural practices and values, family cultural conflict, general parent–child conflict, and parental monitoring at 4 time points from ages 10 to 16. Analyses resulted in a 4-class model for alcohol use, comprising nonusers (62%), early-increasing (10%), adolescent-limited (11%), and late-onset (17%) subgroups, and a 4-class model for cannabis use, including nonusers (74%), early-increasing (8%), occasional use (16%), and high-declining (2%) subgroups. Findings suggested that early language use (higher English at age 10 and lower Spanish at age 12) was a temporally distal marker for several alcohol and cannabis use trajectories, whereas lower traditional family values at ages 14 and 16 were associated with several classes characterized by early substance use. Elevations in familial (parent–child conflict, parental monitoring) risk factors co-occurred in time and generally suggested temporally proximal connections with substance use behavior. Further, there was evidence that a less prominent decline in certain protective factors (e.g., father monitoring) was associated with reductions in substance use. These findings inform the literature by describing youth subgroups with variable risk for substance use development, and suggest modifiable risk factors associated with more frequent substance use trajectories.