The overall objective of this research is to design, develop, and evaluate an onboard high-performance Positron Emission Tomography (PET) that will be integrated into an existing CT image-guided small animal precision X-ray radiation therapy system (CT/RT). This new PET/CT/RT will enable streamlined PET/CT biology functional and organ anatomic dual-modality images to guide the therapy, and provide substantially improved beam targeting accuracy and therapy response evaluation. Both simulation and experiment studies were conducted to investigate the detector design with different resolutions, sensitivities, readout methods, and PET system configurations with different image field of view (FOV) and image performance tradeoffs. The results have shown that the 1.0 mm PET uniform image resolution and ~4% system sensitivity can be achieved within a 80 mm trans-axial and 30 mm axial image FOV. A prototype detector that has been developed and evaluated can achieve energy, coincidence timing, and depth-of-interaction resolutions at ~16%, 1.14 ns, and <3.0 mm respectively. In summary, the overall PET detector and system design studies have been successfully conducted for establishing solid technical solutions to develop the PET/CT/RT system.