PI3K, AKT, and mTOR inhibitors have achieved regulatory approvals in selected cancers, but the clinical efficacy of PI3Kα pathway inhibitors remains limited. This review discusses strategies to improve their efficacy through optimization of inhibitor specificity, patient selection and biomarkers, and identification and abrogation of signaling-related and metabolic mechanisms of resistance. It also highlights approaches to manage prohibitive adverse events and guide the future clinical deployment of PI3K pathway inhibitors in cancer.