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Purpose: We investigated the feasibility of biology-guided radiotherapy (BgRT), a technique that utilizes real-time positron emission imaging to minimize tumor motion uncertainties, to spare nearby organs at risk., Methods: Volumetric modulated arc therapy (VMAT), intensity-modulated proton (IMPT) therapy, and BgRT plans were created for a paratracheal node recurrence (case 1; 60 Gy in 10 fractions) and a primary peripheral left upper lobe adenocarcinoma (case 2; 50 Gy in four fractions)., Results: For case 1, BgRT produced lower bronchus V40 values compared to VMAT and IMPT. For case 2, total lung V20 was lower in the BgRT case compared to VMAT and IMPT., Conclusions: BgRT has the potential to reduce the radiation dose to proximal critical structures but requires further detailed investigation., Competing Interests: JW is a member of the board of advisors and has equity at RefleXion Medical. SM is the founder and CTO of RefleXion Medical. YV is a software architect, RB is a medical physicist, PO is a PET engineer at RefleXion Medical and OO is a clinical scientist at RefleXion Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Seyedin, Bassalow, Mawlawi, Turner, Patel, Mazin, Oderinde, Voronenko, Wages, Olcott, Chang, Balter and Welsh.)