Past studies show that life events (LE) predict mental distress. This research tested whether hemispheric lateralization (HL) moderated the relationship between LE and mental distress. In studies 1 and 2, different instruments for assessing HL were used (questionnaire and neuropsychological test). In both studies, LE or daily hassles were positively correlated with distress (study 1) and with anxiety and depression (study 2), only in people with right but not left HL, controlling for effects of gender. In study 3, experimentally induced stress led to increased perceived stress, again only in participants with right but not left HL. These results show consistently that left HL may protect against adverse effects of LE, hassles or acute stress on well-being. We propose possible mechanisms and future research directions. Copyright © 2014 John Wiley & Sons, Ltd.