Vemurafenib is a targeted therapy against metastatic melanoma. It specifically inhibits the V600 mutated BRAF kinase in the mitogen-activated protein kinase pathway. Only limited data are available on long-term tolerability and efficacy of this drug. Here, we report and discuss six patients from our own clinical practice who were treated with vemurafenib for 16–27 months. Overall, these long-term responders tolerated vemurafenib well during the prolonged period of therapy. Most of the side-effects occurred during the first 6 months of treatment and were transient. The most common persistent side-effect was phototoxicity, which was manageable by precautionary measures or with dose reduction. Interestingly, even permanent dose reductions of 50 % of the standard dose did not abrogate long lasting remissions but improved tolerability, which is a prerequisite of long-term therapy. In addition to our own clinical experience, this article reviews current study results regarding the tolerability and efficacy of long-term vemurafenib therapy.