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Despite the growing arsenal of therapeutics for patients with advanced cancer, not all patients benefit from population-based treatment regimens. Quantitative imaging as a biomarker of biological response can be leveraged both for patient risk stratification and for spatially guided treatment adaptation / intensification. Peripheral blood biomarkers of the immune response and systemic disease burden can complement localized biological imaging assessments and tissue molecular diagnostics. This talk will present an overview of biological response-adaptive radiation therapy in clinical trials, comparing and contrasting different approaches. Ongoing investigations on the clinical utility of quantitative imaging and peripheral blood biomarkers as complements to tissue markers will be summarized in the context of emerging paradigms that seek to personalize radiation and immune modulating systemic therapy combinations.