Purpose: The purpose of this study was to construct a structural equational model to explain and predict burnout in family caregivers of patients with cancer. The study was based on the Stress-Appraisal-Coping Model of Lazarus and Folkman (1984) and Family Stress Theory (Hill, 1958). Methods: Data were collected from July 10 to September 30, 2012 through direct interviews and a self -report questionnaire survey. Participants in this study were 206 family caregivers providing care for patients with cancer in In-patient or Out-patient departments of three different general hospitals located in Busan. Measured variables were exogenous variables (social support and perceived health status) and endogenous variables (perceived stress, hope and burnout). Results: Goodness of fit in the hypothetical model was ${chi}^2=174.07$, TLI=.95, CFI=.97, RMSEA=.08. Perceived health status, perceived stress, and hope showed statistically significant direct effects on burnout of family caregivers. Social support affected burnout of family caregivers indirectly. These variables explained 68.5% of total variance in burnout. Conclusion: The results from this study suggest that perceived stress, perceived health status, and hope should be considered as major influential factors when developing nursing interventions to control burnout of family caregivers (of patients with cancer).