Alpelisib, a selective inhibitor of the phosphatidylinositol 3-kinase (PI3K) alpha isoform, has emerged as a promising therapeutic option for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer harboring PIK3CA mutations. This review provides a comprehensive overview of the clinical efficacy and safety profile of alpelisib in the treatment of PIK3CA-mutated, HR+ advanced breast cancer. We summarize key findings from pivotal clinical trials, including the SOLAR-1 trial, which demonstrated the efficacy of alpelisib in combination with fulvestrant in improving progression-free survival compared to fulvestrant alone in patients with PIK3CA-mutated, HR+ advanced breast cancer. Additionally, we discuss considerations for patient selection, treatment sequencing, and management of adverse events associated with alpelisib therapy. By synthesizing evidence from clinical trials and real-world experience, this review aims to provide oncologists, clinicians, and healthcare providers with practical insights into the use of alpelisib as a targeted therapy for PIK3CA-mutated, HR+ advanced breast cancer.