Some chemotherapy regimens include agents that are mutagenic or clastogenic in model systems. This raises concerns that cancer survivors who were treated before or during their reproductive years may be at increased risks for abnormal reproductive outcomes. However, the available data from offspring of cancer survivors are limited, representing diverse cancers, therapies, time to pregnancies, and reproductive outcomes. Rodent breeding data after paternal exposures to individual chemotherapeutic agents illustrate the complexity of factors that influence the risk for transmitted genetic damage including agent, dose, end point, and germ cell susceptibility profiles that vary across agents. Direct measurements of chromosomal abnormalities in sperm of mice and humans by sperm fluorescent in situ hybridization have corroborated the differences in germ cell susceptibilities. The available evidence indicates that the risk of producing chromosomally defective sperm is highest during the first few weeks after the end of chemotherapy and decays with time. Thus, sperm samples provided immediately after the initiation of cancer therapies may contain treatment-induced genetic defects that will jeopardize the genetic health of offspring.