The study aims to follow trends in the prevalence of licit and illicit substance use between 1984 and 1998 in the Greek general population. Data are drawn from two nationwide cross-sectional household surveys. Probability samples consisted of 4,297 (1984) and 3,759 (1998) 12- to 64-year-old respondents. Regular tobacco smoking in the total sample increased in women and decreased in men while alcohol consumption remained at similar levels. The use of illicit drugs showed a 3-fold increase since 1984 reaching a lifetime prevalence of 19% in males and 6% in females. In contrast, a significant decrease was noted in the unprescribed use of psychoactive medicines, especially among women. Trends in licit and illicit substance use can be explained by sociocultural and policy changes in Greece in the last 15 years.