The incidence of ductal carcinoma in-situ (DCIS) is increasing significantly. DCIS has been demonstrated to arise from terminal duct-lobular units and it is generally accepted that DCIS is a precursor lesion to the majority of invasive ductal carcinoma. DCIS is a highly heterogeneous lesion with variable morphology, clinical presentation and behavior, however, the exact molecular biology of DCIS is not yet resolved. Commonly used markers include estrogen receptor (ER) and progesterone receptor (PR) and less commonly HER2, androgen receptor and TP53. Although significant advances have been made in our knowledge of the molecular pathology of invasive breast carcinoma over the past few decades, few studies focused on DCIS. Several gene expression signature studies suggest that DCIS is genetically advanced and heterogeneous and is a direct precursor of invasive cancer. It is now generally accepted that low grade DCIS is a precursor of low grade invasive carcinoma and high grade DCIS is a precursor of high grade invasive carcinoma. The role of microenvironment appears to be important in the transition of DCIS to invasive disease. Identification of molecular markers that predict the risk of disease progression is needed. Targeting markers that can riskstratify patients with pre-invasive breast cancer would be immensely beneficial in tailoring the treatment of this heterogeneous disease to each individual patient. Recent studies demonstrated the significantly greater rate of concurrent, occult invasive disease in HER2 positive DCIS, suggesting that effective targeting of HER2 in DCIS may be of particular benefit in risk stratification. In addition to ER, PR and HER2, other molecular markers are needed to better predict risk of developing invasive disease and to provide personalized management for patients with DCIS. © 2012 Bentham Science Publishers.