Mutations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway occur in 30%-40% of patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer. For most patients, endocrine therapy with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is the first-line treatment. Recent studies indicate that adding inavolisib, a PI3Kα inhibitor, to palbociclib/fulvestrant benefits patients with endocrine-resistant HR+/HER2- metastatic breast cancer with a PIK3CA mutation. Alpelisib and capivasertib are both US Food and Drug Administration (FDA) approved in combination with fulvestrant in patients with endocrine-resistant HR+/HER2-, PIK3CA-mutant metastatic breast cancer, both with activity in the post-CDK4/6 setting. Capivasertib added to fulvestrant is the first AKT inhibitor to show a significant progression-free survival benefit with a trend for overall survival benefit and the only approved option for patients with phosphate and tensin homolog (PTEN) or AKT alterations. Toxicity profiles of all agents necessitate careful patient selection. Several mutant-selective and pan-mutant-selective novel inhibitors are under investigation with the potential to improve tolerability and efficacy.