Paolo Ascierto, MD of the National Tumor Institute Fondazione G. Pascale, Naples, Italy provides an overview of his talk on the mechanisms of resistance against checkpoint inhibitors in melanoma at the World Congress on Cancers of the Skin (WCCS) and the Congress of the European Association of Dermato-Oncology (EADO) in Vienna, Austria. The mechanisms of resistance are a hot topic because checkpoint inhibitors can cure a good percentage of advanced melanoma patients. The types of resistance are primary, intrinsic or acquired resistance. Resistance is primary resistance when patients do not respond to treatment. Resistance is acquired when patients respond and then progress. Further, there are four main mechanism of resistance and Prof. Ascierto describes them in detail. For example, one mechanism is the increase of regulatory cells in the tumor microenvironment (for example T-reg cells). Another mechanism is the upregulation of the T-cell checkpoint molecules like CTLA4 or PD-L1, which is one of the most important checkpoints.