High cure rates have been achieved for childhood cancers with the use of multimodality treatment, including radiotherapy (RT), chemotherapy (CT), and surgery. For a small number of cancers, RT is used as a definitive treatment modality but is more commonly used as one component of a multimodality approach. Technological advances in the precision of RT treatment planning and delivery have resulted in improved outcomes and a more favorable toxicity profile. The timing of RT also needs to be carefully planned to reduce undesired side effects. In this chapter, we review the principles of multimodality cancer treatment for childhood cancer. We also describe the sequence in which other modalities vis-a-vis RT are employed to treat common pediatric cancers. Treatment of difficult-to-cure childhood cancers, such as high-risk neuroblastoma involves the use of several modalities sequentially to achieve the best outcome. Conversely, the treatment burden for low-stage and low-risk tumor types is carefully reduced to minimize or avoid the treatment-related late effects.