This article reports on the findings of a qualitative study based on three focus-groups of individuals (N = 32) living with Systemic Lupus Erythematosus (SLE). The themes that emerged indicated a high vulnerability for self-reported feelings of depression. The four key challenges included: (1) feeling depressed that they are not who they used to be, (2) feelings of depression and anxiety related to coping with the uncertainty of the illness, (3) physical and emotional fatigue of living with a chronic illness, and (4) coping with the financial strain of the illness. These psychosocial challenges should be considered in screening, assessment, and treatment planning for social work service with this population.