Stress is an inevitable part of school leadership. However, little is known about the main causes of school leaders' stress in Ireland, and their association with workplace wellbeing and leaders' daily responsibilities. The current paper aimed to address this gap. A cross-sectional, mixed-methods design survey was conducted with 267 school leaders in the Republic of Ireland, the majority of whom were at least 5 years in their role. The qualitative results demonstrated that three main issues causing leaders stress were (1) relational issues, (2) systemic issues relating to the external pressures, and (3) systemic issues relating to their daily responsibilities. A further, multiple regression identified that 29% of the variance in leaders' stress was explained by daily responsibilities with two, in particular, predicting their higher stress levels (1) employee relations (beta = 0.24), and (2) new teacher or substitute teacher appointments (beta = 0.22). Finally, 25% of the variance in leaders' stress was explained by work-related wellbeing, in particular, four factors predicted leaders' stress levels (1) perceiving their work as meaningful, (2) high levels of physical health, (3) high levels of positive affect, and (4) low levels of negative affect. The implications of the study are discussed along with the recommendations for future research.