Biology-guided radiation therapy (BgRT) is a significant therapy method in radiotherapy (RT) that enhances treatment precision and effectiveness by utilizing biological markers. Traditional RT methods, using high-energy radiation to destroy cancer cells, have evolved through technological advancements such as linear accelerator (Linac) systems and imaging techniques. Intensity-Modulated Radiotherapy (IMRT) and Stereotactic Body Radiotherapy (SBRT) have improved targeting and reduced damage to healthy tissues. However, conventional RT has some challenges in treating multiple tumors simultaneously, particularly in metastatic cancer. BgRT addresses these limitations by incorporating Positron Emission Tomography (PET) to guide radiation based on real-time biological activity. This approach allows for personalized treatment plans tailored to the genetic and molecular profiles of tumors, enhancing treatment effectiveness and minimizing side effects. BgRT’s ability to monitor tumors dynamically during treatment enables immediate adjustments, optimizing therapeutic outcomes. BgRT machine system, an FDA-approved device for IMRT, SABR, and BgRT technology by integrating PET imaging with radiation delivery. Quality assurance studies have demonstrated the system’s dosimetric precision and imaging accuracy, supporting its clinical efficacy. BgRT is particularly promising for treating oligometastatic and polymetastatic diseases, offering precise, personalized therapies that target multiple tumors in a single session. Future advancements in imaging techniques, PET tracers, and adaptive radiotherapy systems are expected to further enhance BgRT’s capabilities. Continuous research and development in this field are crucial for improving cancer treatment outcomes and expanding the therapeutic options available in radiation oncology.