Because of remarkable progress in therapy, long-term survival is expected for 80% of children and adolescents diagnosed with cancer. Infertility remains one of the most common and life-altering complications experienced by adults treated for cancer during childhood. Surgery, radiation, or chemotherapy that negatively affects any component of the hypothalamic-pituitary-gonadal axis may compromise reproductive outcomes in childhood cancer survivors. The risk of infertility is generally related to the tissues or organs involved in cancer and the specific type, dose, and combination of cytotoxic therapy. In addition to anticancer therapy, age at treatment, sex, and likely genetic factors influence the risk of permanent infertility. When possible, contemporary protocols limit cumulative doses of cytotoxic therapy in an effort to optimize reproductive potential. If sterilizing therapy is required for cancer control, then fertility preservation measures should be explored before initiation of therapy. For childhood cancer survivors who maintain fertility, health risks to offspring resulting from their cancer treatment are major concerns. Radiation affecting ovarian and uterine function has been linked to pregnancy complications, including spontaneous abortion, preterm labor, fetal malposition, and low birth weight. The risk of congenital malformations, genetic disorders, and cancer appears to be low, with the exception of cancer risk in offspring born to survivors with germline cancer-predisposing mutations. This review summarizes research about cancer treatment factors affecting fertility and pregnancy outcomes of childhood cancer survivors. The data presented should facilitate the delivery of preventive counseling and age- and sex-appropriate interventions to optimize reproductive outcomes in childhood cancer survivors.