Interest in the application of mindfulness-based intervention for the treatment of psychological disorders and promotion of wellbeing has grown exponentially in recent years. Mindfulness-based interventions have been found to be beneficial for treatment of various forms of psychopathology as well as improve psychological wellbeing and enhance physical health. Little research has investigated for whom and under what conditions training people to use mindfulness-based therapeutic techniques is most effective. Recent studies have found evidence that individual differences in personality traits are associated with mindfulness. For example, neuroticism has been found to be negatively associated with mindfulness. These associations raise the possibility that individual differences in personality may potentially moderate the effectiveness of mindfulness-based interventions. In the present study we draw on Gray's revised Reinforcement Sensitivity Theory (r-RST) to examine relationships between personality traits, mindfulness and psychological distress. We found that the Flight, Fight, Freeze system mediated the relationship between trait mindfulness and psychological distress, while trait mindfulness moderated the relationship between the Flight, Fight, Freeze system and psychological distress. Both results are consistent with the suggestion that acquiring the skills from learning and practicing mindfulness techniques is potentially useful, particularly for threat-sensitive individuals with low to moderate levels of trait mindfulness.