Background: Mast cell chymase may be both pro-inflammatory and anti-inflammatory during infection and tissue damage. Results: Human and mouse chymases modulate extracellular levels of the alarmins Hsp70, biglycan, HMGB1, and IL-33. Conclusion: Mast cell chymase degrades alarmins and may limit inflammation. Significance: Identifying the physiological chymase substrates is crucial for understanding the role of chymase in immune responses and could aid in drug development.