To present the novel Symptom Cluster Experience Profile (SCEP) framework for guiding symptom research in adult survivors of childhood cancers and other subgroups at risk for high symptom burden.Empirically derived model of symptom cluster experience profiles, existing theoretical frameworks, and data-based literature on symptoms and quality of life in adult survivors of childhood cancers.In a previous study, the authors generated a preliminary model to characterize subgroups of adult survivors of childhood cancers with high-risk symptom cluster profiles. The authors developed the SCEP framework, which depicts symptom cluster experiences as subgroup-specific profiles that are driven by multiple sets of risk and protective factors. The risk and protective factors may directly and indirectly contribute to or alleviate symptoms through their effects on systemic stress. Systemic stress instigates and sustains the symptom experience that, in turn, is expressed through negative diffusion into other components of quality of life, such as functional status, general health perceptions, and overall quality of life.The SCEP framework is an initial approach to unbundle the complex heterogeneity that underlies the clustering of symptoms. By measuring a wide range of risk and protective factors in future studies of adult survivors of childhood cancers and other subgroups at risk for high symptom burden, further development and validation of the SCEP framework will occur.The SCEP framework can be used to specify mechanisms underlying symptom cluster profiles and derive interventions targeted to high-risk symptom profiles. Findings from future studies can be translated to risk-based surveillance and symptom management clinical practice guidelines.