Breast cancer continues to be the most commonly diagnosed cancer worldwide and represents a leading cause of cancer-related mortality among women. Next-Generation Sequencing (NGS) has played an important role in providing mechanistic insights into the transcriptional, epigenetic and genomic nature of the disease, however, most of the work has focused on in vitro studies. The lack of in vivo characterization has led to an over-simplified account of molecular events, and limited our understanding of clonal variation and tumor heterogeneity in breast cancer. Hence, the combination of NGS with in vivo models provides an opportunity to bridge the gap between mechanistic models and the underlying pathophysiology of breast cancer. This collection will focus on emerging techniques in digital and molecular pathology, using lesion-specific tissue samples to assess transcriptomic and epigenetic aberrations in breast cancer. The goal of this collection is to provide protocols for execution of high-throughput genomic experiments, including: (1) Methods of assessing clonal variation and pathobiology of pre-cancerous lesions (RNA-seq), (2) Methods of validating genomic events such as transcription factor binding in tissue samples in vivo (ChIP-seq), (3) Methods of assessing defects in epigenetic regulation in breast cancer such as high-throughput methylase-assisted bisulfite sequencing (MAB-seq), and (4) Other high-throughput methods that allow for characterization of genomic aberrations in breast cancer tissue samples.