Breast cancer (BC) is the most common cancer among women worldwide. The fifth edition of the World Health Organization (WHO), edited in 2019, is still based on morphology and incorporates intrinsic subtypes based on immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and the proliferation marker Ki67. This classification categorizes all cancers into four molecular groups: luminal A, B, Her2-enriched, and triple-negative breast cancers (TNBC). The advent of precision medicine improves the use of high-throughput sequencing technologies such as Next-Generation Sequencing (NGS). According to the 2024 ESMO/PMWG guidelines, NGS is recommended to manage BC only for specific druggable biomarkers. Nevertheless, comprehensive molecular profiling through next-generation sequencing (NGS) is also utilized as a diagnostic tool, particularly in challenging or ambiguous BC cases, or as an invaluable research tool, offering deep insights into unsolved questions or allowing the discovery of new unexplored horizons in the era of precision medicine.