Background: Genome-wide association studies identified novel breast cancer susceptibility variants that could be used to predict breast cancer in asymptomatic women. This review and modeling study aimed to investigate the current and potential predictive performance of genetic risk models. Methods: Genotypes and disease status were simulated for a population of 10,000 women. Genetic risk models were constructed from polymorphisms from meta-analysis including, in separate scenarios, all polymorphisms or statistically significant polymorphisms only. We additionally investigated the magnitude of the odds ratios (OR) for 1 to 100 hypothetical polymorphisms that would be needed to achieve similar discriminative accuracy as available prediction models [modeled range of area under the receiver operating characteristic curve (AUC) 0.70-0.80]. Results: Of the 96 polymorphisms that had been investigated in meta-analyses, 41 showed significant associations. AUC was 0.68 for the genetic risk model based on all 96 polymorphisms and 0.67 for the 41 significant polymorphisms. Addition of 50 additional variants, each with risk allele frequencies of 0.30, requires per-allele ORs of 1.2 to increase this AUC to 0.70, 1.3 to increase AUC to 0.75, and 1.5 to increase AUC to 0.80. To achieve AUC of 0.80, even 100 additional variants would need per-allele ORs of 1.3 to 1.7, depending on risk allele frequencies. Conclusion: The predictive ability of genetic risk models in breast cancer has the potential to become comparable to that of current breast cancer risk models. Impact: Risk prediction based on low susceptibility variants becomes a realistic tool in prevention of nonfamilial breast cancer. Cancer Epidemiol Biomarkers Prev; 20(1); 9-22. (C) 2011 AACR.