"In modern radiotherapy complex radiation fields are applied on cancer patients to eradicate cancer cells, while sparing the surrounding healthy tissue. In stark contrast, irradiation systems for small animals bear almost no resemblance to this paradigm. Usually these systems only administer large radiation fields which can not be modulated in their spatio-temporal aspect. Consequently, many animal radiation experiments have little relevance for human radiotherapy. To allow studies of radiation effects on tumors and healthy tissues in small animals and the synergistic effects of radiation and other treatment modalities (chemotherapy, gene therapy) it engineering of the next generation of animal irradiation devices is needed now. In this proposal we describe the development of a versatile small animal irradiation device capable of delivering precise radiation fields with modulation of the spatio-temporal-energetic aspects. A dynamic applicator for a kilovolt x-ray device will mimic the delivery of modern human radiotherapy. In addition, energy modulation of the radiation beams will allow studies with dose enhancing agents such as gold particles. A treatment planning system will be devised, based on Monte Carlo simulations, which will take tissue heterogeneities into account. A conversion of small animal tomographic images into accurate geometries needed for the Monte Carlo dose calculations will be developed. An on-board cone-beam tomographic imager will be implemented to enable the acquisition of 3D images during radiation treatment, again mimicking the state of the art in human radiotherapy. The image-guided small animal radiation system, with unprecedented accuracy and versatility in its spatio-temporal-energetic radiation patterns, combined with integrated real-time imaging capabilities, will facilitate uncovering a wealth of data relevant for radiation oncology and radiobiology."