The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives.