The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is aberrantly activated in cancer. Activation of this pathway has been observed in all three main molecular subtypes of breast cancer (hormone receptor-positive, human epidermal growth factor receptor 2-positive, and triple-negative breast cancer) and, therefore, represents an attractive therapeutic target. Various agents that target the PI3K/AKT/mTOR pathway are under clinical development, including pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. Due to the potential for enhanced activity of PI3K inhibitors in combination with other agents, various novel combinations are under investigation in breast cancer. This review will largely focus on the pan-PI3K inhibitor buparlisib and the α-specific PI3K inhibitor alpelisib (BYL719), which are currently in clinical development. Early clinical evidence for the use of buparlisib has been encouraging, and several Phase II and III studies are underway to assess buparlisib in combination with other antineoplastic agents in breast cancer. Alpelisib has also demonstrated encouraging preclinical and preliminary clinical activity. To assess if PI3K pathway alterations (i.e. PIK3CA mutation) can predict better outcome to buparlisib and/or alpelisib, various approaches have been taken across studies, including patient stratification and selection according to PI3K status in the tumor. In addition, large-scale analyses using techniques such as high-throughput next-generation sequencing will be also used. The approach selected and the challenges faced for the clinical development of the PI3K inhibitors, buparlisib, and alpelisib in breast cancer are presented. [ABSTRACT FROM AUTHOR]