The current model of human breast cancer progression proposes a linear multi-step process which initiates as flat epithelial atypia (FEA), progresses to atypical ductal hyperplasia (ADH), evolves into DCIS and culminates in the potentially lethal stage of invasive ductal carcinoma. For several decades a major challenge to human breast cancer research has been the identification of the molecular alterations associated with the different stages of breast cancer progression. Until recently, progress in attaining this goal has been hampered by technical limitations associated with applying advanced molecular technologies to the microscopic preinvasive stages of breast tumorigenesis. Recent advances in comprehensive, high-throughput genetic, transcriptomic and epigenetic technologies in combination with advanced microdissection and ex vivo isolation techniques have provided for a more complete understanding of the complex molecular genetic and molecular biological inter-relationships of the different stages of human breast cancer evolution. Here we review the molecular biological data suggesting that breast cancer develops and evolves along two distinct molecular genetic pathways. We also briefly review gene expression and epigenetic data that support the view of the tumour microenvironment as an important co-conspirator rather than a passive bystander during human breast tumorigenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.