Using a predominately Mexican-origin Latino sample of 5th grade students from the Southwestern United States, this study examined the relative effects of perceived discrimination and acculturation stress on substance use, and it assessed whether these effects were moderated by linguistic acculturation or time in the United States. Although rates of substance use were generally low in the sample, given the young age of the participants, over half (59%) of the sample perceived some discrimination, and almost half (47%) experienced some acculturation stress. Spanish-dominant and bilingual youth perceived more discrimination than English-dominant youth, whereas youth who have been in the United States five or fewer years perceived more discrimination than youth with more time in the United States. Youth who were Spanish-dominant or were recent arrivals experienced the most acculturation stress, with levels declining as linguistic acculturation and time in the United States increased. Multiple regression estimates indicated that perceived discrimination was associated with larger amounts and higher frequency of recent substance use and an array of substance use attitudes, such as stronger intentions to use substances, espousal of pro-drug norms, more positive substance use expectancies, and peer approval of substance use. Although acculturation stress was not associated with substance use, it was positively associated with several substance use attitudes, which are known antecedents of actual use. With a few exceptions, linguistic acculturation and time in the United States did not moderate the effects of perceived discrimination or acculturation stress. (Contains 2 tables and 2 notes.)