This textbook is a comprehensive review of the physics of heterogeneous radiation and is linked, through a multidisciplinary approach, to clinical applications and biological considerations of heterogenous radiation. Fundamental principles of Spatially Fractionated Radiation Therapy (SFRT), techniques and technologies, dosimetric properties of SFRT, planning methods, documentation, standardized reporting metrics and clinical practice recommendations are comprehensively reviewed. The current status and results of clinical patient studies are presented, which have the potential to advance the management of bulky and advanced tumors. Potential biological underpinnings are reviewed that may challenge the current radiobiological understanding of radiation response and radiation therapy design parameters. Such multidisciplinary understanding is a critical foundation as the field of heterogeneous radiation rapidly advances in technological development and clinical investigation.