For the past century, subcutaneous allergen-specific immunotherapy has been the state-of-the-art treatment for IgE-mediated allergic disease. Current research on allergen-specific immunotherapy is focused on enhancing its efficacy, safety, and patient convenience with the goal of offering a broadly accepted treatment option. There is a growing interest in intralymphatic allergen-specific immunotherapy because it is a highly efficacious and safe treatment route that requires only 3 injections. Concurrently, epicutaneous allergen-specific immunotherapy is attracting increasing attention because of its capacity to offer a safe, needle-free, and potentially self-administrable treatment option for IgE-mediated allergic diseases. In this article, we discuss the principles and immunologic rationale of these unconventional routes of allergen-specific immunotherapy while highlighting their developmental process and clinical relevance.