Hyperglycemia is a common adverse event (AE) associated with phosphatidylinositol-3-kinase inhibitors (PI3Kis) and considered an on-target effect. Presence of hyperglycemia is associated with poor outcomes in patients with cancer, and there is need for further refinement of hyperglycemia prevention and mitigation strategies in patients receiving PI3Kis. In this review, the authors highlight effective strategies for preventing PI3Ki-induced hyperglycemia before and during treatment as well as hyperglycemia management. Prior to initiating treatment with PI3Ki, identify baseline risk factors of patients at increased risk for developing hyperglycemia, which include older age, obesity, and glycosylated hemoglobin (HbA1c) 5.7%-6.4% (prediabetes or Type 2 diabetes). To prevent new-onset hyperglycemia, optimize blood glucose, and recommend a low-carbohydrate (60-130 g/day) diet along with regular exercise to all patients prior to initiating the PI3Ki. Prophylactic metformin may be considered in all patients starting a PI3Ki with HbA1c