End of life (EOL) caregiving can be a daunting and challenging endeavor as caregivers adjust to the ever-changing care demands associated with dying. Increased personal care, assisting with symptom and medication management, and attending to the emotional and spiritual needs of the dying person require caregivers to learn new tasks and to assume new roles such as social worker, nurse, and chaplain. As families continue to play an essential role in meeting the health care needs of their dying loved ones, it is imperative for social workers to understand the complexities of the end of life caregiving experience in order to better serve this population. One way to better understand this experience is by examining it within the context of the stress process model of caregiving. This model provides a comprehensive way to examine the relationship among multiple risk and protective factors within the “caregiver-in-environment” context. Using a secondary dataset, the best fit predictive model of caregiver depression included a mix of sociodemographic characteristics, primary objective and subjective stressors, and mediating variables. Two protective factors, social support and the fulfillment of spiritual needs lessened the effects of caregiver depression among the most vulnerable caregivers. Findings from this study help to bridge the gap between theory and social work practice. The stress process model of caregiving is a well-tested theoretical model, which can be utilized to guide social workers in developing comprehensive assessment measures and interventions that target specific aspects and sources of stress within the EOL caregiving experience.