Mast cell disorders are rare, chronic diseases involving unpredictable physical symptoms ranging in severity, duration, and frequency. Almost two-thirds of participants with these disorders (n = 180) experienced clinically meaningful depressive symptoms. Depressed mood was associated with somatic symptomatology, poorer quality of life, lower resilience, and indirectly with ways of coping. Newly developed measures for this population performed psychometrically well. There was no gender difference in depression but women reported greater use of several ways of coping, greater disease-related distress, poorer quality of life, and more symptoms. Results underscore the need for further research and development of effective psychosocial interventions for this population.