Although gender differences in the consumption and abuse of alcohol and drugs are frequently reported, the etiology of these differences has received limited attention. The present study applied biometric genetic analyses to determine whether self-report questionnaire items assessing problem alcohol and drug use are influenced by gender-specific genetic and environmental influences. The sample consisted of 693 volunteer general population twin pairs (209 monozygotic female, 138 monozygotic male, 170 dizygotic female, 82 dizygotic male, 94 dizygotic opposite-sex twin pairs). Heritability analyses showed that most aspects of drug and alcohol problems were differentially heritable by gender. Significant additive genetic effects were found only in males, whereas in females, most substance use problems were wholly determined by environmental factors. In both genders, non-shared environmental factors accounted for the largest proportion of the variance, and further gender-by-genotype analyses showed that these influences were not gender specific, but rather were common to males and females. Some preliminary evidence was also obtained that the use of illicit drugs may be etiologically distinct from the use of licit drugs in females and males.