Exposure of cells to ionizing radiation induces damage in the DNA. The adverse consequences of such exposures depend on the amount of the DNA damage induced as determined by the absorbed dose, as well as by its form as determined by the linear energy transfer. In addition to physical determinants, biological factors critically affect radiation response. Cells have the ability to sense DNA damage, and to activate repair pathways that efficiently remove such damage and restore the integrity of the DNA. Highly sophisticated mechanisms further enable cells to actively stall growth and division after sensing DNA damage. Such inhibitory processes, termed checkpoints, may optimize repair and minimize the adverse consequences of DNA damage. We review the fundamental principles underlying checkpoints as they have emerged from active research in the last few years and discuss briefly their relevance to the practice of medical and radiation oncology.