Adverse drug reactions (ADRs) rank as one of the top ten leading causes of death and illness in the developed world. In cancer therapy, more patients are surviving cancer than ever before, but 40% of cancer survivors suffer life-threatening or permanently disabling severe ADRs and are left with long-term sequelae. ADRs are often more frequent and more severe in children, and the consequences for children who experience a severe ADR can be catastrophic. Pharmacogenomics has the potential to improve the safety of these drugs. This review highlights severe ADRs that can occur in cancer therapy that are more frequent and more severe in children, and the pharmacogenomics research that aims to understand, predict, and ultimately prevent these severe reactions.