Radiation biology has entered the era of precision oncology, and this article reviews time-tested factors that determine the effects of fractionated radiation therapy in a wide variety of tumor types and normal tissues: the association of tumor control with radiation dose, the importance of fractionation and overall treatment time, and the role of tumor hypoxia. Therapeutic gain can only be achieved if the increased tumor toxicity produced by biological treatment modifications is balanced against injury to early-responding and late-responding normal tissues. Developments in precision oncology and immuno-oncology will allow an emphasis on treatment individualization and predictive biomarker development.