Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) solicits research projects that investigate actionable synthetic vulnerabilities that can be conditionally paired with tumor responses to radiation therapy. The goal of the Precision Approaches in Radiation Synthetic Combinations (PAIRS) program is to develop radiation-synthetic combination strategies and facilitate their adoption into the precision medicine toolkit toward building new and effective anticancer treatments. Early synthetic lethality–based therapeutic strategies in oncology primarily focused on targeting fixed mutations or genomic abnormalities. More recently, however, it has become clear that clinical benefit is often determined by context-dependent vulnerabilities arising from the intrinsic mutational landscape and adaptive tumor responses. This NOFO is unique in its scope, supporting innovative cancer therapy strategies that explicitly exploit context-dependent effects of radiation therapy (RT) using drug-radiation combinations. The central premise of the PAIRS is that these conditional RT-induced responses can be leveraged to create or enhance actionable vulnerabilities that synergize with molecularly targeted agents for better outcomes. A defining feature of PAIRS is its emphasis on precision, scientific rigor, and reproducibility, aligned with NIH’s scientific priorities. Radiation effects are clinically titratable through advances in delivery accuracy and flexibility, including dose, schedule, and spatial targeting. These capabilities enable the rational design of conditional RT-synthetic combination strategies that preferentially exploit tumor-specific essentialities while sparing normal tissues, thereby enhancing the therapeutic index by optimizing biological response. This NOFO consolidates the prior exploratory/developmental and research project funding opportunities to streamline the application process and maintain momentum in developing approaches that target actionable vulnerabilities within the defined radiation research scope. The applicants may submit either for exploratory/developmental research projects with a project period of up to 2 years or for research projects with a project period of 4 to 5 years.