Skin cancer, as the most physically accessible malignancy, allows for the greatest variety in treatment innovation. The last 2 decades have seen striking increases in the life expectancies of those diagnosed with malignant melanoma. However, many cases remain in which disease prevails against standard treatment, and those patients rely on continuing ingenuity. Drugs that can be injected directly into patients' tumors have become increasingly promising, not least for the reduction in side effects observed. Intratumoral therapy encompasses a wide array of agents, from chemotherapeutic drugs to cancer vaccines. While each show some efficacy, those agents which regulate the immune system likely have the greatest potential for preventing disease progression or recurrence. Recent research has highlighted the importance of the presence of cytotoxic T cells and of keeping regulatory T cells in check. Thus, manipulating the tumor microenvironment is a need in skin cancer therapy, which intratumoral delivery can potentially address. In order to find the best approach to each person's disease, more studies are needed to test intralesional agents in combination with currently approved therapies and with each other.