The aim was to explore the association of self-esteem and resilience with smoking and cannabis use among adolescents, separately for gender. A sample of 3694 adolescents (mean age 14.3 years) from elementary schools in Slovakia filled out the Rosenberg Self-esteem scale, the Resiliency scale and answered questions about cigarette and cannabis use. Logistic regression models showed associations between negative self-esteem and risky behavior, but only among boys. Regarding resilience, structured style and family cohesion were associated with a lower probability of smoking and cannabis use among both boys and girls. In contrast, social competence increased the probability of smoking and cannabis use among both groups. Negative self-esteem seems to play an important role regarding smoking and cannabis use among boys. Resilience seems to have mixed effects, some aspects being protective while other aspects increase the likelihood of smoking and use of cannabis. These results imply that the prevention of substance use should target not only specific individual characteristics, but also the possible risk or protective influences of the social environment, i.e. the family and social network.