The optimal duration of therapy in patients receiving immune-checkpoint inhibitors (ICIs) is a new but crucial question that has arisen owing to the observation of durable remissions in >85% of patients with metastatic melanoma who stop receiving an anti-PD-1 antibody after a complete response (CR). Long-term treatment-free remissions have also been seen, albeit much less frequently, in patients receiving ICIs for other forms of cancer who have a CR. Despite these promising observations, the optimal duration of treatment with ICIs remains unknown and requires further investigation in randomized controlled trials. In the absence of prospective data, some general criteria to guide the safe cessation of ICIs can be proposed, at least for patients with melanoma, in whom ICI cessation after a confirmed CR and at least 6 months of treatment is generally deemed safe. In this Perspective, we describe the available data on ICI interruption in patients with melanoma and in those with various other cancers. We also address the patient management implications of stopping ICI therapy.