Personalized cell therapy targeting tumor antigens with expanded tumor-infiltrating lymphocytes (TILs) has shown great promise in metastatic melanoma (MM) since the 90s. However, MM was first-in line to benefit from the wave of checkpoint inhibitors (CPI), which shifted the focus of immunotherapy almost fully to immune CPI. Still, the majority of patients fail to benefit from CPI treatment, raising the intriguing question on how TIL therapy may fit into the changing landscape of melanoma treatment. We took advantage of data from a unique cohort of patients with MM treated with T-cell therapy in consecutive clinical trials at our institution across the last 10 years. Based on detailed data on patient characteristics, pre-TIL and post-TIL treatments and long-term follow-up, we were able to address the important issue of how TIL therapy can be positioned in the current CPI era. We found that previous progression on anticytotoxic T-lymphocyte-associated protein 4 do not seem to harm neither rate nor duration of response to TIL therapy. Importantly, even in the hard-to-treat population of patients who progressed on antiprogrammed cell death protein 1 (anti-PD-1), an objective response rate of 32% was achieved, including durable responses. Yet, median progression-free survival was reduced in this anti-PD-1 refractory population. Trial registration number: ClinicalTrials.gov ID: NCT00937625, NCT02379195 and NCT02354690.