Abstract We are entering the era of precision medicine in which cancer screening, prevention and treatment will be tailored to each individual. The progress made in this field is due, in part, to advances in our understanding of cancer risk and tumor biology. The challenge before us is to harness this knowledge and apply it in the clinical setting. Breast cancer screening provides an excellent opportunity to test the value of precision medicine in the real world. In this report we describe the process of designing a model of personalized breast cancer screening. Methods Risk factors were selected that have the greatest impact, have been validated and can be measured across a population. A risk model was selected that is highly calibrated, has been validated in a large screening cohort and is easy to apply in a large population of women. An expert committee was convened that set risk thresholds for stratifying women into groups that will be recommended to undergo biennial, annual or every six month screening. Risk thresholds and screening schedules are in accordance with the United States Preventive Services Task Force breast cancer screening recommendations. Results Risk factors: Age, race/ethnicity, personal history of breast biopsies and benign breast disease, family history, breast density and breast cancer-associated genetic mutations and single nucleotide polymorphisms (SNPs) were chosen as the risk factors that will be used to determine breast cancer risk. Risk model: The Breast Cancer Surveillance Consortium risk model will be used to calculate a woman's 5-year risk and will be modified by a polygenic risk score based on 81 SNPs. Risk thresholds: Women will be recommended to undergo biennial screening mammography when they reach the age of 50 or have the risk of an average 50 year-old woman (1.3% 5-year risk). Women will be advised to undergo annual screening if they are at increased risk of developing an interval cancer (women in their forties with extremely dense breasts and women at increased risk of developing estrogen receptor negative breast cancer based on their SNPs). Women will be recommended to undergo annual mammography and annual MRI if they are found to be gene mutation positive, have the risk of a BRCA1 mutation carrier (6% 5-year risk) or have a history of mantle radiation. Discussion Selecting the appropriate risk factors and risk model and determining risk thresholds are key components of designing a personalized breast cancer screening model. Personalized screening may be the way forward, but this can only be determined within the setting of a randomized controlled trial. We will conduct such a trial to determine if personalized screening is as safe as, less morbid than, more preferred by women than and enables prevention when compared to annual screening. The WISDOM (Women Informed to Screen Depending on Measures of risk) study will compare risk-based screening to annual screening within the Athena Breast Health Network with support from the Patient-Centered Outcomes Research Institute. Our intent is that this trial will provide us with the data that we need to determine the safest and most effective way to screen women for breast cancer in the era of precision medicine. Citation Format: Thompson CK, Fiscalini AS, Donnellan P, Kaplan CP, Madlensky L, Eklund M, Ziv E, van't Veer LJ, Tice JA, Esserman LJ. Breast cancer screening in the precision medicine era. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-02-08.