Interleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.“,”Interleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.