Chronic illness can have a profound impact on the lives of individuals across biopsychosocial domains. The focus of this chapter is on crosscutting issues in the conceptualization of psychological adjustment to chronic conditions, as well as theoretical frameworks and empirical findings regarding determinants of adjustment to chronic disease. Individuals with chronic illness are at heightened risk for distress and dysfunction; however, marked heterogeneity in adjustment is apparent across individuals and diseases. Psychological adjustment to chronic illness is considered across interrelated biopsychosocial dimensions that unfold over time. A model of adjustment to chronic illness is presented with a focus on the sociocultural, interpersonal, intrapersonal, and disease-related contexts that confer risk across adjustment domains. The model includes the potential of appraisal and coping processes in determining adjustment. Recommendations are to continue to examine multiple dimensions of adjustment in prospective, longitudinal studies; advance the knowledge base on the influence of macro-level contextual influences on disparities in adjustment to chronic disease; study the mechanistic role of biobehavioral factors in disease-related adjustment; and build empirical validation of theory-driven clinical interventions to support adjustment across diverse groups.