The father, like the mother, can transmit genetic defects to his offspring that are detrimental for normal development and a healthy life. Epidemiological studies have identified associations between several paternal exposures and abnormal reproductive outcomes, but these types of studies are inherently complex and expensive, and the risk factors for the paternal contribution to abnormal reproductive outcomes remain poorly understood. Several sensitive methods have been developed for detecting mutations and chromosomal damage directly in sperm. These assays are potential bioindicators for paternal risk factors for infertility, spontaneous abortions, aneuploidy syndromes, and genetic diseases in children. Among these methods, fluorescence in situ hybridization (FISH) has been adapted for the detection of numerical and structural chromosomal abnormalities in the sperm of an expanding number of species, including humans and rodents. Sperm FISH has identified several potential paternal risk factors such as age, drugs, lifestyles, and various environmental/occupational exposures. Here, we summarize the status of the development and usage of these sperm-FISH assays and suggest strategies for prioritizing chemical agents for epidemiological investigations to assess paternal risk for abnormal reproductive outcome.