The popular theory six degrees of separation is used in this review as an analogy to relate all radiosensitization to oxygen. As the prime mover of all radiosensitizers, the pervasive influence of oxygen has consciously or unconsciously influenced the direction of research and development and provided the benchmark against which all other compounds and approaches are measured. It is the aim of this review to develop the six degrees of separation from oxygen analogy as a unifying framework for conceptually organizing the field and for giving context to its varied subspecializations and theories. Under such a framework, it would become possible for one area to consider questions and problems found in other areas of radiosensitization, using a common analogy, that would allow for further development and unification of this multifaceted discipline. In this review, approaches to the development of radiosensitizers and the current state of research in this field are discussed, including promising new agents in various stages of clinical development.