Data for the research were collected as part of a study that examined normal drug education practices in middle schools in Winston-Salem/Forsyth County, N.C. Data were collected yearly from students in sixth through ninth grades for school years 1990-91, 1991-92, 1992-93, and 1993-94. Student self-report data from multiple cohorts were available for analysis. In addition to asking students about current and previous drug use, they were queried on 12 potential mediating variables related to substance- use prevention: beliefs about consequences, decision making skills, goal-setting skills, self-esteem, stress management skills, social and life skills, perceived alternatives to drug use, assistance skills, resistance skills, the incongruence between values and substance use, manifestations of a commitment to not use substances, and normative beliefs. Findings show that although some deterioration of key mediators occurs developmentally among all adolescents, the deterioration is more severe for students that initiate substance use. Further, the rate of deterioration associated with the onset of substance use is more evident for some mediators (e.g., normative beliefs, commitment, and lifestyle incompatibility) than for others (e.g., goal-setting and self-esteem). Finally, evidence indicates that the mediators that have the greatest deterioration significantly vary across substances. In other words, the degree of deterioration in mediators that should have a substantial influence on adolescent substance use varies across alcohol, tobacco, marijuana, and inhalant use. Implications of the findings for program development and intervention strategies are discussed. 7 tables, 1 figure, 32 references, and appended survey questions related to individual items in mediating scales