The use of checkpoint inhibitors is revolutionizing the treatment outcomes in many cancer types. Besides this benefit, using checkpoint inhibitors may produce unique toxicity called immune-related adverse events (irAE). The onset of irAE is related to epitope spreading of T-cells, causing upregulation of cytotoxic T-cells and helper 1 and 17 T-cells, the latter being recently investigated as one of the main characters in the irAE scenery. With other mechanisms like depletion of Foxp3+ CD4-lymphocytes, the proliferation of plasmacytes and autoantibodies production, direct cytotoxicity, and increase of proinflammatory cytokines, the immune system is in the state of autoaggression to host tissues. Dual blockade of CTLA-4 and PD-1:PD-L1 causes the most and highest grade adverse events. Also, some patient-related factors, tumor histology, and microbiome composition play a role. Many laboratory tests are associated with the risk of irAE in pretreatment and on-treatment setting. Prophylaxis of irAE is not recommended at this point. Corticosteroids remain the first-line treatment for most irAE, but a detailed understanding of the mechanisms of each organ-specific irAE lead to the use of immunosuppressive and cytokine-targeted therapies. In this chapter, we discuss known aspects of checkpoint inhibitors’ toxicity pathogenesis and how they can be implemented for better management when irAE occur.