A solid scientific basis now supports the concept that cytotoxic T lymphocytes can specifically recognize and destroy melanoma cells. Over the last decades, clinicians and basic scientists have joined forces to advance our concepts of melanoma immunobiology. This has catalyzed the rational development of therapeutic approaches to enforce melanoma-specific T cell responses. Preclinical studies in experimental mouse models paved the way for their successful translation into clinical benefit for patients with metastatic melanoma. A more thorough understanding of how melanomas develop resistance to T cell immunotherapy is necessary to extend this success. This requires a continued interdisciplinary effort of melanoma biologists and immunologists that closely connects clinical observations with in vitro investigations and appropriate in vivo mouse models: From bedside to bench to barn and back.