Cancer progression is a dynamic process of clonal adaptation to changing microenvironments. From the single founder cell until the clinical detection of tumours, there are consecutive clonal expansions and a constant acquisition of genetic and epigenetic alterations, events that contribute to the generation of intra-tumor heterogeneity. In breast cancer intra-tumor heterogeneity can arise from the differentiation of stem-like cells along with the clonal selection during tumor progression, and represents a major challenge for the design of effective therapies. To infer breast cancer progression and its response to particular treatments it is important to understand the origins of the inter- and intra-tumor heterogeneity and the forces that control tumor evolution. Insights about the evolution of breast cancer heterogeneity would contribute to the design of most effective therapeutic strategies to target the tumors at single clon level. This review is intended to give a general overview about the origins of breast cancer heterogeneity and its impact in the clinical management of the disease.