Interleukin-2 (IL-2) is a potent cytokine discovered over four decades ago, involved in immune regulation and effector T cell expansion and differentiation. High-dose IL-2 treatment has been approved for renal cell carcinoma and melanoma, achieving durable responses in a subset of patients. However, its clinical utility is limited by its short half-life, severe vascular toxicity, and the activation of regulatory T cells. To overcome these limitations, novel engineering strategies are being developed to create safer and more effective IL-2-based therapies. These include modifications to increase IL-2's half-life, such as pegylation and fusion to albumin or antibodies, as well as targeted delivery to tumor-specific effector lymphocytes. Combining IL-2 with other immunotherapies, such as PD-1/L1 pathway blockade, has shown improved anti-tumor efficacy. This review discusses the biological characteristics of IL-2 and its receptors, its efficacy and toxicities in cancer patients, and the efforts to develop novel and safer IL-2 therapies.Interleukin-2 (IL-2) is a potent cytokine discovered over four decades ago, involved in immune regulation and effector T cell expansion and differentiation. High-dose IL-2 treatment has been approved for renal cell carcinoma and melanoma, achieving durable responses in a subset of patients. However, its clinical utility is limited by its short half-life, severe vascular toxicity, and the activation of regulatory T cells. To overcome these limitations, novel engineering strategies are being developed to create safer and more effective IL-2-based therapies. These include modifications to increase IL-2's half-life, such as pegylation and fusion to albumin or antibodies, as well as targeted delivery to tumor-specific effector lymphocytes. Combining IL-2 with other immunotherapies, such as PD-1/L1 pathway blockade, has shown improved anti-tumor efficacy. This review discusses the biological characteristics of IL-2 and its receptors, its efficacy and toxicities in cancer patients, and the efforts to develop novel and safer IL-2 therapies.