Promotion of mental well-being and prevention of emotional and behavioral problems are suggested to go hand in hand. The present study examined the association between subjective well-being (SWB) and psychopathology and investigated the etiology of this association in a large population-based cohort study of adolescent twins (n = 9,136) and their non-twin siblings (n = 1,474) aged 12-20 years. Phenotypic, genetic, and environmental correlations between SWB and psychopathology were obtained from multivariate genetic modeling conditional on sex. An SWB factor score was used based on measures of subjective happiness, satisfaction with life, and quality of life. Psychopathology was obtained from all syndrome and broad-band scales of the Dutch version of the ASEBA Youth Self Report. Males reported significantly higher levels of SWB than females. Females reported significantly more internalizing problems while males report significantly higher levels of externalizing behavior. In both sexes, significant negative associations were found between SWB and psychopathology, with the strongest associations seen for SWB and the YSR syndrome scale anxious/depression behavior. The observed associations were primarily explained by genetic correlations while non-shared environmental influences were mainly domain specific. The genetic liability to lower levels of SWB are indicative of a genetic liability to higher levels of psychopathology, suggesting that it might be feasible to screen for emotional and behavioral problems before clear signs are present by screening on indices of subjective well-being.