Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, which can be administered intralesionally in patients with unresectable metastatic melanoma. Treatment with T-VEC monotherapy for early metastatic melanoma can be an elegant alternative to systemic treatment. It is also suitable for elderly and frail patients. With real word data and more recent RCTs we tried to identify the optimal patient selection for T-VEC monotherapy. Monitoring of TVEC treatment with (PET-CT) imaging, clinical observation and histological biopsies can be useful in clinical decision making. For head & neck melanoma, there are less alternative options such as isolated limb perfusion, and T-VEC can be considered as a treatment option. Even when patients suffer from recurrence of disease after a prior complete clinical response to T-VEC, re-introduction of T-VEC monotherapy shows promising responses. The surgical management of melanoma is changing rapidly, with the improvements in systemic therapies, in adjuvant and neo-adjuvant settings, and personalized medicine. Adequate (American Joint Committee on Cancer) staging and risk stratification in melanoma are vital to choose the best therapeutic option for each melanoma patient. Sentinel node evaluation is complicated by several factors, sometimes leading to false positive or negative results with a risk of over- or undertreatment in this current era of adjuvant systemic therapy. Innovations such as a localized index initial tumor positive node removal after neo-adjuvant immunotherapy in patients with stage III melanoma could be used as a response indicator to guide the extent of completion lymph node dissection.